4-hydroxypiperidine derivatives having antiarrhythmic activity

ABSTRACT

The present invention relates to a compound represented by the following formula (I) or a salt thereof, or a pharmaceutical composition containing the compound as an effective ingredient:  
                 
 
     (wherein A represents, for example, phenyl group substituted with R 1  and R 2  or unsubstituted thienyl group; R 1  and R 2  each independently represent, for example, hydrogen atom, halogen atom or lower alkoxycarbonyl group; R 3  represents, for example, hydrogen atom; R 4  represents, For example, lower alkyl group; R 5  represents, for example, lower alkoxy group; R 6  represents, for example, hydrogen atom; R 7  and R 8  each represent, for example, hydrogen atom, respectively; X represents, for example, a single bond; Y represents, for example, methylene group or benzylidene group substituted with R 1 ; and Z represents, for example, methylene group.) The compounds according to the present invention that do not suppress the transient sodium current of the cardiac muscle and do not manifest proarrhythimic activity is useful as a therapeutic agent for preventing and/or treating arrhythimia and for preventing sudden death.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The present invention relates to novel 4-hydroxypiperidinederivatives, a method for manufacturing thereof, and a pharmaceuticalcomposition comprising at least one of the derivatives as activeingredients, in particular an antiarrythmic agent capable of oraladministration.

[0003] 2. Description of Related Art

[0004] The heart can regularly beat when the excitation initiated at thesinus node conducts in a correct order. Arrythmia is generated whenabnormal excitation and conduction to the heart are caused. Accordingly,the mechanism of onset of arrythmia is categorized into three groups of(1) abnormal excitation (2) abnormal conduction of excitation and (3) acombination of abnormal excitation and abnormal conduction ofexcitation.

[0005] Vaughan Williams, Singh and Houswirth have categorizedantiarrythmic agents into four classes based on their action in thefirst half of 1970's. Since then, this classification—namely the VaughanWilliams classification—has been utilized as a standard classificationof the antiarrythmic agents. This classification method is excellent inthat it briefly expresses features of pharmacological action of variousantiarrythmic agents, and has been utilized by many physicians. Thisclassification method roughly classifies the antiarrythmic agents intofour classes of the class I to class IV.

[0006] The antiarrythmic agents classified into the class I aremedicines which have mainly a sodium channel blocking activity, andreduce the maximum upstroke velocity of depolarization at the 0-th phaseof the action potential, thereby reducing the conduction speed. Theclass I agents are further classified into sub-classes of Ia, Ib and Icbased on their effects on the action potential duration. The class Iagents are featured in reduction of the cardiac contractility as aresult of reduced intracellular calcium concentration due to activationof a sodium/calcium exchange mechanism, because the intracellular sodiumconcentration is reduced by blocking the sodium channel. Reduction ofthe cardiac contractility is one of crucial adverse effects of the classI antiarrythmic agents comparable to a proarrhythmic activity directlyrelated to suppression of conduction due to the sodium channel blockingactivity.

[0007] The antiarrythmic agents belonging to the class II are medicineswhich mainly have a β-receptor blocking activity. Stimulation of the β(β₁)-receptor in the cardiac muscle cells with catecholamines activatesadenylate cyclase, enhances production of cyclic AMP and increases theinward calcium current. As a result, physiological automaticity of thesinus node as well as abnormal automaticity in the morbid cardiac muscleare exacerbated. Action potential duration is also shortened byactivating various ion channels related to repolarization. Although theclass II antiarrythmic agents are effective against the arrhythimiarelated to the sympathetic nerve by their antagonistic activity againstthe action of catecholamines, adverse effects such as suppression ofcardiac function due to β-receptor blocking activity is worried.

[0008] The antiarrythmic agents belonging to the class III are definedas the medicines with a primary action to retard repolarization andprolong of the action potential duration. These agents suppressarrythmia by prolonging refractory period as a result of prolongation ofthe action potential duration. It was made clear from recent studiesthat blocking action on the potassium channel is mainly responsible forthe principal action of such agent, and a term “pottasium channelblocker” is currently synonymous with the class III agent. The class IIIagents are advantageous over the class I agents in that the former showsno suppression on cardiac contractility. On the other hand, “torsades depointes” as a result of a prolonged QT interval is a crucial andpotentially lethal adverse effect common to the class III agents.

[0009] The antiarrythmic agents classified into the class IV is definedas medicines the main action of which is the blocking of the calciumchannel. Although the agents are used for treating arrythmia caused byacceleration of automaticity in the sinus node and arrythmia related tothe atrioventricular node, an antiarrythmic agent, for example,verapamil may weaken contraction force of the cardiac muscle.

[0010] In the Cardiac Arrythmia Suppression Trial (CAST) operated in1989 in USA, Flecainide and Encainide belonging to the class Iantarrythmic agents were used for post-myocardial infarction patientswith silent and mild symptoms of ventricular extrasystole, and it wasfound that incidence of sudden death increases in the group administeredwith test drugs (Echt, D. A. et al., The new England Journal ofMedicine, Vol. 324, pp.781-788, 1991). In other words, it was shown thatsuppression of ventricular extrasystole by the class I agents does notalways suppress severe arrythmia such as ventricular fibrillation thatis considered to cause sudden death. This research report aroused theneed of paying attention to an appropriate use of the antiarrythmicagents, besides affording novel antiarrythmic agents to be developed. Inplace of conventional chemicals represented by powerful sodium channelblockers that have been used in the CAST study and suppressdepolarization process of the cardiac muscle, potassium channel blockersthat prolong the refractory period by prolonging the repolarizationprocess have been expected to be the antiarrythmic agents for preventingsudden death. Clinical trials with amiodarone and sotalol at an earlystage have accelerated this trend, and the potassium channel blockerwithout severe side-effects of amiodarone (for example, interstitialpneumonia and fibrosis of the lung) has been largely expected. However,developments of d-sotalol, E-4031 and sematilide have been suspendedsince it was proved that the incidence of “torsades de pointes”accompanied by the QT prolongation was unexpectedly high in clinicaltrials in Japan as well as those in the USA and Europe with large scalein addition to the increase of mortality by these drugs. Noantiarrythmic agent that can suppress sudden death of the arrythmiapatients with basal diseases such as ischemic heart diseases and heartfailure while avoiding the severe side-effects of amiodarone (forexample, interstitial pneumonia and fibrosis of the lung) have beendiscovered in the present time. The large problems involved in drugtherapy of arrythmia are (1) the class I and class III agents thataffect conduction velocity and action potential duration by acting onthe normal cardiac muscle cannot be safe antiarrythmic agents since theyhave proarrythmic action, and (2) the class II and class IV agents areonly effective to limited symptoms of arrythmia. Accordingly,developments of novel type of antiarrythmic agents that are highly safewhile avoiding the drawbacks of the antiarrythmic agents belonging tothe class I to class IV classification are desired.

[0011] The sodium current normally observed in the excitable cells israpidly inactivated after being promptly activated by a stimulus(depolarization), and thus the observed current is a transient inwardcurrent. The class I agent suppresses this transient sodium current, anddecreases the maximum upstroke velocity of depolarization at the 0-thphase of the action potential to reduce the conduction velocity.However, some kinds of the sodium current are slowly or seldominactivated, and these currents are considered to be involved inadjustment of physiological excitability of the neurons and cardiacmyocytes. This sort of current is called as a persistent sodium current.This current is suggested to be involved in abnormal excitability of theneurons (for example, epileptic attack and ischemia) and morbidity ofthe cardiac myocytes (for example, onset of arrythmia), as reported bySegal, M. M. et al. (Journal of Neurophysiology, Vol. 77, pp. 3021-3034,1997) and Ju, Y-K et al. (Journal of Physiology, Vol. 497, No. 2, pp.337-347, 1996).

[0012] While lidocaine and quinidine are reported as the compounds forsuppressing the persistent sodium current in the cardiac muscle (Ju, Y-Ket al., British Journal of Pharmacology, Vol. 107, pp. 311-316, 1992),these compounds belong to the class I agent, and exhibit no specificitysince they suppress the persistent sodium current as well as thetransient sodium current. While phenytoin is reported to suppress thesecurrents in the neurons (Segal et al., Journal of Neurophysiology, Vol.77, pp. 3021-3034, 1997), phenytoin also has no specificity since it iscategorized in the class I antiarrythmic agent.

[0013] Although 4-hydroxypiperidine derivatives have been reported to bethe compounds having an analgesic activity in Japanese PatentApplication Laid-open No. Sho 50-36471, an antiarrythmic action asdescribed in the compound according to the present invention has notbeen disclosed therein. Although piperidine derivatives having anantiarrythmic activity have been disclosed in Japanese PatentApplication Laid-open No. Sho 59-225161, the compounds have differentstructures from the compounds according to the present invention, andare suspected of having side-effects adverse on the activity of thenormal cardiac muscle. Therefore, the compounds of the publication havenot been developed as commercially available drugs. While JapaneseNational Patent Publication No. Hei 6-50093 discloses 4-substitutedpiperidine derivatives having the calcium blocking activity as neuroprotective agents, the antiarrythmic activity as disclosed in thecompounds according to the present invention has not been disclosed.

[0014] Not only desired pharmaceutical activities but also long-termsafety are required in the development of medicines. In addition, severecriteria in various tests on absorption, distribution, metabolism andexcretion should be satisfied. For example, problems to be examined andsolved include interaction among the drugs, desentitization andtolerance, absorption at the digestive tract after oral administration,transfer speed into the small intestines, absorption velocity and firstpass effect, internal organ barrier, binding to proteins, induction ofdrug metabolizing enzymes, the excretion pathway, clearance in the bodyand the methods of application (application sites, methods and objects). However, compounds satisfying all these requirements can be seldomfound.

[0015] The antiarrythmic agent also involves such general problems asdescribed above in developing as a medicine. The antiarrythmic agent isfurther required to avoid several problems as hitherto described such asproarrythmic activity, cardiac depression, torsades de pointesaccompanied by prolongation of the QT interval, and increased incidenceof sudden death.

SUMMARY OF THE INVENTION

[0016] The object of the present invention is to provide a novelcompounds having an antiarrythmic activities with less side-effect andhigh grade of safety. Another object of the present invention is toprovide methods for manufacturing the compounds Ad and to providemedicines and pharmaceutical compositions containing the compounds. Inparticular, the object of the present invention is to provide a drug,particularly an anti-arrythmic agent, capable of orally administering tomammals including humans, wherein at least one problem in theconventional art, for example, an proarrythmic action, a cardiacdepression and torsades de pointes accompanied by a prolonged QTinterval involved in the conventional drugs have been conquered. Themedicines also have less proarrythmic action and cardiac depression sothat conduction and action potential duration of the normal cardiacmyocytes are not affected, and sudden death can be prevented.

DETAILED DESCRIPTION OF THE INVENTION

[0017] The inventors of the present invention have found that, throughintensive studies for obtaining chemicals having an excellentantiarrythmic action with high safety, novel 4-hydroxypiperidinederivatives and salts thereof have a suppressing action againstcontracture of the isolated cardiac muscle caused by veratrine, oraladministration of the chemicals is effective in an ischemia-reperfusionmodel, have no effects on the normal activity in cardiac myocytes, andhave less adverse effects while being highly safe, thereby completingthe present invention.

[0018] The first embodiment of the present invention is to provide acompound represented by the formula (I):

[0019] (wherein A represents a phenyl group, naphthyl group ormonocyclic aromatic heterocyclic group each substituted by R¹ and R²; R¹and R² each independently represent groups arbitrarily selected from agroup comprising hydrogen atom, halogen atom, trifluoromethyl group,cyano group, lower alkoxycarbonyl group, amino group unsubstituted ormono- or di-substituted by lower alkyl group, lower alkanoylamino groupunsubstituted or substituted by fluorine atom, unprotected or protectedhydroxyl group, lower alkoxy group, lower alkyl group, trifluoromethoxygroup, nitro group, phenyl group, phenoxy group, unprotected orprotected carboxyl group, carbamoyl group unsubstituted or mono- ordi-substituted by lower alkyl group, lower alkanoyl group, loweralkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl groupand sulfamoyl group unsubstituted or mono- or di-substituted by loweralkyl group, or R¹ and R² together represent alkylenedioxy group; R³represents hydrogen atom or lower alkyl group; R⁴ represents hydrogenatom, lower alkyl group or lower alkanoyl group; R⁵ and R⁶ eachindependently represent a group arbitrarily selected from a groupcomprising hydrogen atom, halogen atom, lower alkoxy group unsubstitutedor mono-substituted by unprotected or protected hydroxyl group, loweralkyl group unsubstituted or mono-substituted by unprotected orprotected hydroxyl group, phenoxy group, lower alkenyloxy group orunprotected or protected hydroxyl group; X represents a single bond, agroup: —CH(OH)—, oxygen atom or carbonyl group; Y represents loweralkylene group, lower alkylidene group or benzylidene group substitutedby R¹, Y may form 5- or 6-membered ring together with X and carbon atomson a benzene ring when A is phenyl group; Z represents a single bond ormethylene group unsubstituted or substituted by a group arbitrarilyselected from a group comprising a lower alkyl group, lower alkoxy groupor unprotected or protected hydroxyl group; and R⁷ and R⁸ eachindependently represent hydrogen atom or lower alkyl groups, providedthat a case that R⁵ and R⁶ simultaneously represent hydrogen atoms isexcluded) and pharmaceutically acceptable salts thereof and apharmaceutical composition containing these compounds as activeingredients.

[0020] Preferable substituents or preferable combinations thereof in thecompound represented by the formula (I) are shown below. However, thepresent invention is by no means restricted thereto.

[0021] A is preferably phenyl group or thienyl group each substituted byR¹ and R², more preferably phenyl group substituted by R¹ and R² or anunsubstituted thienyl group. In addition, it is preferable that A isphenyl group substituted by R¹ and R², and R¹ is bound to apara-position (4-position) relative to —X—.

[0022] R¹ and R² each are preferably hydrogen atom, halogen atom,trifluoromethyl group, cyano group, lower alkoxycarbonyl group, loweralkanoylamino group unsubstituted or substituted by fluorine atom, loweralkoxy group, lower alkyl group, trifluoromethoxy group, nitro group orlower alkylthio group, and more preferably hydrogen atom, halogen atom,trifluoromethyl group, cyano group, lower alkoxycarbonyl group ortrifluoromethoxy group.

[0023] As the combinations of R¹ and R², it is preferable that R¹ ishydrogen atom, halogen atom, trifluoromethyl group, cyano group, loweralkoxycarbonyl group, lower alkanoylamino group unsubstituted orsubstituted by fluorine atom, lower alkoxy group, lower alkyl group,trifluoromethoxy group, nitro group or lower alkylthio group, and R² ishydrogen atom or halogen atom. It is more preferable that R¹ is hydrogenatom, halogen atom, trifluoromethyl group, cyano group, loweralkoxycarbonyl group or trifluoromethoxy group, and R² is hydrogen atomor halogen atom.

[0024] R³ is preferably hydrogen atom.

[0025] R⁴ is preferably lower alkyl group or lower alkanoyl group, morepreferably lower alkyl group.

[0026] R⁵ is preferably lower alkoxy group, lower alkyl group or phenoxygroup, more preferably C₂₋₆ alkoxy group, and further preferablystraight chaine or branched C₂₋₄ alkoxy group.

[0027] R⁶ is preferably hydrogen atom, halogen atom, unprotected orprotected hydroxyl group or lower alkyl group unsubstituted ormono-substituted by unprotected or protected hydroxyl group, and morepreferably hydrogen atom.

[0028] As the combination of R⁵ and R⁶, it is preferable that R⁵ is C₂₋₆alkoxy group, and R⁶ is hydrogen atom, and it is more preferable that R⁵is straight chian or branched C₂₋₄ alkoxy group, and R⁶ is hydrogenatom.

[0029] R⁵ is preferably bound to a para-position (4-position) relativeto —NR⁴—.

[0030] X is preferably a single bond or a group: —CH(OH)—, and morepreferably a single bond.

[0031] Y is preferably C₁₋₂ alkylene group or benzylidene groupsubstituted by R¹, and more preferably methylene group or benzylidenegroup substituted by R¹.

[0032] Y preferably forms indanyl group when A is a phenyl group and 5-to 6-membered ring is formed together with X and carbon atoms on thebenzene ring.

[0033] Z is preferably a single bond or methylene group unsubstituted orsubstituted by hydroxyl group, and more preferably methylene group.

[0034] R⁷ and R⁸ each are preferably hydrogen atoms.

[0035] As the combination of the substituents is preferable that thebonding position of R⁵ is at the para-position (4-position) relative tothe group —NR⁴—, R⁷ and R⁸ each are hydrogen atom, X is a single bond,and Y is C₁₋₂ alkylene group or benzylidene group substituted by R¹.

[0036] It is preferable that A is phenyl group or thienyl group eachsubstituted by R¹ and R², R⁴ is lower alkyl group, and Z is a singlebond or methylene group.

[0037] It is preferable that R¹ is hydrogen atom, halogen atom,trifluoromethyl group, cyano group, lower alkoxycarbonyl group ortrifluoromethoxy group, R² is hydrogen atom or halogen atom, R³ ishydrogen atom, R⁵ is C₂₋₆ alkoxy group, R⁶ is hydrogen atom, and Y ismethylene group benzylidene group substituted by R¹.

[0038] The compounds according to the present invention are thecompounds represented by the formula (I) or salts thereof. Concreteexamples of the compounds having combinations of preferable substituentsare as follows.

[0039] In the formula (I), it is shown a compound or a salt thereof inwhich A is phenyl group substituted by R¹ and R² or unsubstitutedthienyl group; R¹ is hydrogen atom, halogen atom, trifluoromethyl group,cyano group, lower alkoxycarbonyl group or trifluoromethoxy group; R² ishydrogen atom or halogen atom; R³ is hydrogen atom; R⁴ is methyl group;R⁵ is straight chain or branched C₂₋₄ alkoxy group with its bondingposition at the para-position (4-position) relative to the group —NR⁴—;R⁶ is hydrogen atom; R⁷ is hydrogen atom; R⁸ is hydrogen atom; X is asingle bond; Y is methylene group or benzylidene group substituted byR¹; and Z is methylene group. In this case, the formula (I) may beexpressed by the formula (II):

[0040] (wherein A′ represents a phenyl group substituted by R¹ and R² orunsubstituted thienyl group, —O(C₂₋₄ Alk) represents straight chain orbranched C₂₋₄ alkoxy group, and Ya represents methylene group orbenzylidene group substituted by R¹).

[0041] The second embodiment of the present invention is to provide apharmaceutical composition comprising the compound represented by theformula (I) or a pharmaceutically acceptable salt thereof as activeingredients.

[0042] The third embodiment of the present invention is to provide anantiarrythmic agent comprising the compound represented by the formula(I) or a pharmaceutically acceptable salt thereof as acectiveingredients. The antiarrythmic agent is capable of oral administration.

[0043] The fourth embodiment of the present invention is to provide amethod for manufacturing a compound represented by the formula (I)-a ora salt thereof which both R⁷ and R⁸ in the formula (I) are hydrogenatoms:

[0044] (wherein A, R³, R⁴, R⁵, R⁶, X, Y and Z have the same meanings asdefined above), comprising the following process (a) or (b).

[0045] Process (a)

[0046] A process characterized by reacting the compound represented bythe formula (VI):

[0047] (wherein A, R³, X and Z have the same meanings as defined above,R⁴′ represents hydrogen atom or lower alkyl group, R⁵′ and R⁶′ have thesame meanings as defined in R⁵ and R⁶, or represent lower alkoxycarbonylgroup, and Y′ has the same meaning as defined in Y. or represents C₁₋₂alkylenecarbonyl group or carbonyl group) under reducing conditions.

[0048] Process (b)

[0049] A process characterized by reacting a compound represented by theformula (VIII):

[0050] (wherein R³, R⁴′, R⁵′, R⁶′ and Z have the same meanings asdefined above) under reducing conditions to form a compound representedby the formula (X):

[0051] (wherein R³, R⁴′, R⁵, R⁶ and Z have the same meanings as definedabove) and reacting the obtained compound of the formula (X) with acompound represented by the formula (IX):

[0052] (wherein A, X and Y′ have the same meaning as defined above, andQ represent hydrogen atom, hydroxyl group, halogen atom or lower alkylgroup) in the presence or absence of a base when —Y′ and -Q togetherrepresent halogenated alkyl, in the presence or absence of an acidcatalyst under reducing conditions when —Y′ and -Q together representaldehyde or ketone, or using a condensation agent when —Y′ and -Qtogether represent carboxylic acid, followed by reduction reaction.

[0053] The fifth embodiment of the present invention is to provide amethod for manufacturing a compound represented by the following formula(I)-b or a salt thereof which R⁷ and R⁸ in the formula (I) aresimultaneously hydrogen atom and Z is Z′:

[0054] (wherein A, R³, R⁴, R⁵, R⁶, X and Y have the same meanings asdefined above, and Z′ represents methylene group unsubstituted orsubstituted by a group arbitrarily selected from a group comprisinglower alkyl group, lower alkoxy group or unprotected or protectedhydroxyl group), and uses the following process (c) or (d).

[0055] Process (c)

[0056] A process characterized by adding a compound represented by theformula (XI):

[0057] (wherein R⁴′, R⁵, R⁶ and Z′ have the same meanings as definedabove and W represents hydrogen atom or halogen atom) to a compoundrepresented by the formula (XII):

[0058] (wherein A, X and Y′ have the same meanings as defined above) andalkylating the generated hydroxy group according to the necessity toobtain a compound represented by the formula (VI′):

[0059] (wherein A, R³, R⁴′, R⁵, R⁶, X, Y′ and Z′ have the same meaningsas defined above) and reacting the obtained compound (VI′) underreducing conditions.

[0060] Process (d)

[0061] A process characterized by adding the compound represented by theformula (XI):

[0062] to a compound represented by the formula (XIII):

[0063] (wherein P represents a protective group used for an amino group)and alkylating the obtained hydroxyl group according to the necessity toobtain a compound represented by the formula (VII′):

[0064] (wherein R³, R⁴′, R⁵, R⁶, Z′ and P have the same meanings asdefined above), and followed by deprotection and reduction reactions toobtain a compound represented by the formula (X′):

[0065] (wherein R³, R⁴′, R⁵, R⁶ and Z′ have the same meaning as definedabove), which is allowed to react with a compound represented by theformula (IX):

[0066] in the presence or absence of a base when —Y′ and -Q togetherrepresent halogenated alkyl, in the presence or absence of an acidcatalyst under a reducing condition when —Y′ and -Q together representaldehyde or ketone groups, or using a condensation agent when —Y′ and -Qtogether represent carboxylic acid, followed by conducting reductionreaction.

BEST MODE FOR CARRYING OUT THE INVENTION

[0067] The present invention will be described in detail hereinafter.The compounds according to the present invention are compoundsrepresented by the formula (I) or pharmaceutically acceptable saltsthereof:

[0068] (wherein A represents phenyl group, naphthyl group or monocyclicaromatic heterocyclic group each substituted by R¹ and R²; R¹ and R²each independently represent groups arbitrarily selected from a groupcomprising hydrogen atom, halogen atom, trifluoromethyl group, cyanogroup, lower alkoxycarbonyl group, amino group unsubstituted or mono- ordi-substituted by lower alkyl group, lower alkanoylamino groupunsubstituted or substituted by fluorine atom, unprotected or protectedhydroxyl group, lower alkoxy group, lower alkyl group, trifluoromethoxygroup, nitro group, phenyl group, phenoxy group, unprotected orprotected carboxyl group, carbamoyl group unsubstituted or mono- ordi-substituted by lower alkyl group, lower alkanoyl group, loweralkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl groupand sulfamoyl group unsubstituted or mono- or di-substituted by loweralkyl group, or R¹ and R² together represent alkylenedioxy group; R³represents hydrogen atom or lower alkyl group; R⁴ represents a hydrogenatom, lower alkyl group or lower alkanoyl group; R⁵ and R⁶ eachindependently represent a group arbitrarily selected from a groupcomprising hydrogen atom, halogen atom, lower alkoxy group unsubstitutedor mono-substituted by unprotected or protected hydroxyl group, loweralkyl group unsubstituted or mono-substituted by unprotected orprotected hydroxyl group, phenoxy group, lower alkenyloxy group orunprotected or protected hydroxyl group; X represents a single bond, agroup: —CH(OH)—, oxygen atom or carbonyl group; Y represents loweralkylene group, lower alkylidene group or benzylidene group substitutedby R¹, Y may form 5 or 6-membered ring together with X and carbon atomon a benzene ring when A is phenyl group; Z represents a single bond ormethylene group unsubstituted or substituted by a group arbitrarilyselected from a group comprising a lower alkyl group, lower alkoxy groupor unprotected or protected hydroxyl group; and R⁷ and R⁸ eachindependently represent hydrogen atom or lower alkyl groups, providedthat a case that R⁵ and R⁶ simultaneously represent hydrogen atoms isexcluded).

[0069] In the definitions of the groups in the structural formulaaccording to the present invention, the “monocyclic aromaticheterocyclic” means 5 or 6-membered ring containing one or twohetero-atoms and includes, for example, pyrrolyl group, furyl group,thienyl group, imidazolyl group, oxazolyl group, thiazolyl group,pyridyl group or pyrimidinyl group.

[0070] The “halogen atom” includes fluorine atom, chlorine atom, bromineatom and iodine atom.

[0071] The term “lower” means straight, branched or cyclic carbon chainwith a carbon number of 1 to 6, unless otherwise stated. Accordingly,the “lower alkyl group” includes, for example, methyl group, ethylgroup, propyl group, isopropyl group, butyl group, isobutyl group,sec-butyl group, tert-butyl group, pentyl group, isopentyl group,3-pentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group,2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexylgroup, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group,1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutylgroup, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group,3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group,1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group,1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group, cyclopropylgroup, cyclobutyl group, cyclopentyl group, cyclohexyl group,cyclopropylmethyl group, 1-cyclopropylethyl group, 2-cyclopropylethylgroup, cyclobutylmethyl group, 2-cyclobutylethyl group orcyclopentylmethyl group.

[0072] The term “lower alkyl group mono-substituted by hydroxyl group”means a group which an arbitrary hydrogen atom on the lower alkyl groupis substituted by hydroxyl group. Examples of it include a hydroxymethylgroup, 1-hydroxyethyl group, 2-hydroxyethyl group,1-hydroxy-1-methylethyl group, 1-hydroxypropyl group, 2-hydroxypropylgroup, 3-hydroxypropyl group, 1-hydroxy-1-methylpropyl group,1-hydroxybutyl group, 2-hydroxybutyl group, 3-hydroxybutyl group,4-hydroxybutyl group, 1-hydroxy-1-methylbutyl group, 1-hydroxypentylgroup, 2-hydroxypentyl group, 3-hydroxypentyl group, 4-hydroxypentylgroup, 5-hydroxypentyl group, 1-hydroxy-1-methylpentyl group,1-hydroxyhexyl group, 2-hydroxyhexyl group, 3-hydroxyhexyl group,4-hydroxyhexyl group, 5-hydroxyhexyl group, 6-hydroxyhexyl group,1-hydroxycyclopropyl group and 1-hydroxycyclopropylmethyl group.

[0073] The “lower alkoxycarbonyl group” includes a methoxycarbonylgroup, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonylgroup, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonylgroup, tert-butoxycarbonyl group, pentyloxycarbonyl group,isopentyloxycarbonyl group, neopentyloxycarbonyl group,tert-pentyloxycarbonyl group, hexyloxycarbonyl group,cyclopropyloxycarbonyl group, cyclobutyloxycarbonyl group,cyclopentyloxycarbonyl group, cyclohexyloxycarbonyl group,cyclopropylmethyloxycarbonyl group, 1-cyclopropylethyloxycarbonyl group,2-cyclopropylethyloxycarbonyl group, cyclobutylmethyloxycarbonyl group,2-cyclobutylethyloxycarbonyl group or cyclopentylmethyloxycarbonylgroup.

[0074] The term “the amino group unsubstituted or mono- ordi-substituted by lower alkyl group” means amino group in which one ortwo hydrogen atoms of the amino group may be substituted by the “loweralkyl group”. Example of it include amino group, methylamino group,ethylamino group, propylamino group, isopropylamino group, butylaminogroup, isobutylamino group, pentylamino group, isopentylamino group,hexylamino group, isohexylamino group, dimethylamino group, diethylaminogroup, dipropylamino group, diisopropylamino group, dibutylamino group,dipentylamino group, ethylmethylamino group, methylpropylamino group,ethylpropylamino group, butylmethylamino group, butylethylamino group orbutylpropylamino group.

[0075] The “lower alkanoylamino group unsubstituted or substituted byfluorine atoms” include, for example, a formylamino group, acetylaminogroup, monofluoroacetylamino group, difluoroacetylamino group,trifluoroacetylamino group, propionylamino group, 2-fluoroaropionylamino group, 3-fluoropropionylamino group,2,2-difluoropropionylamino group, 2,3-difluoropropionylamino group,3,3,3-trifluoropropionylamino group, 2,2,3,3-tetrafluoropropionylaminogroup, pentafluoropropionylamino group, butyrylamino group,isobutyrylamino group, valerylamino group, isovalerylamino group,pivaloylamino group or hexanoylamino group.

[0076] The “lower alkoxy group” include, for example, a methoxy group,ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxygroup, sec-butoxy group, tert-butoxy group, pentyloxy group,isopentyloxy group, 3-pentyloxy group, tert-pentyloxy group,neopentyloxy group, 2-methylbutoxy group, 1,2-dimethylpropoxy group,1-ethylpropoxy group, hexyloxy group, cyclopropyloxy group,cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group,cyclopropylmethyloxy group, 1-cyclopropylethyloxy group,2-cyclopropylethyloxy group, cyclobutylmethyloxy group,2-cyclobutylethyloxy group or cyclopentylmethyloxy group.

[0077] The “lower alkoxy group mono-substituted by hydroxyl group” meansa group in which an arbitrary hydrogen atom except at the 1-position ofthe lower C₂₋₆ alkoxy group is mono-substituted by hydroxyl group.Examples of it include 2-hydroxyethoxy group, 2-hydroxy-1-methylethoxygroup, 2-hydroxypropoxy group, 3-hydroxypropoxy group, 2-hydroxybutoxygroup, 3-hydroxybutoxy group, 4-hydroxybutoxy group, 2-hydroxypentyloxygroup, 5-hydroxypentyloxy group, 2-hydroxyhexyloxy group,6-hydroxyhexyloxy group, 2-hydroxycyclopropyloxy group,2-hydroxycyclobutyloxy group, 2-hydroxycyclopentyloxy group or3-hydroxycyclopentyloxy group.

[0078] The “carbamoyl group unsubstituted or mono- or di-substituted bylower alkyl groups” means a carbamoyl group in which one or two hydrogenatoms on the nitrogen atom in the carbamoyl group may be substituted byaforesaid “lower alkyl group”. Example of it include carbamoyl group,methylcarbamoyl group, ethylcarbamoyl group, propylcarbamoyl group,isopropylcarbamoyl group, cyclopropylcarbamoyl group, butylcarbamoylgroup, isobutylcarbamoyl group, pentylcarbamoyl group,isopentylcarbamoyl group, hexylcarbamoyl group, isohexylcarbamoyl group,dimethylcarbamoyl group, diethylcarbamoyl group, dipropylcarbamoylgroup, diisopropyl-carbamoyl group, dibutylcarbamoyl group,dipentylcarbamoyl group, ethylmethylcarbamoyl group,methylpropylcarbamoyl group, ethylpropylcarbamoyl group,butylmethylcarbamoyl group, butylethylcarbamoyl group, orbutylpropylcarbamoyl group.

[0079] Examples of the “lower alkanoyl group” include formyl group,acetyl group, propionyl group, butyryl group, isobutyryl group, valerylgroup, isovaleryl group, pivaloyl group or hexanoyl group.

[0080] Examples of the “lower alkylthio group” include a methylthiogroup, ethylthio group, propylthio group, isopropylthio group, butylthiogroup, isobutylthio group, sec-butylthio group, tert-butylthio group,pentylthio group, isopentylthio group, tert-pentylthio group,neopentylthio group, 2-methylbutylthio group, 1,2-dimethylpropylthiogroup, 1-ethylpropylthio group, hexylthio group, cyclopropylthio group,cyclobutylthio group, cyclopentylthio group, cyclohexylthio group,cyclopropylmethylthio group, 1-cyclopropylethylthio group,2-cyclopropylethylthio group, cyclobutylmethyl-thio group,2-cyclobutylethylthio group or cyclopentylmethylthio group.

[0081] Examples of the “lower alkylsulfinyl group” include amethylsulfinyl group, ethylsulfinyl group, propylsulfinyl group,isopropylsulfinyl group, butylsulfinyl group, isobutylsulfinyl group,sec-butylsulfinyl group, tert-butylsulfinyl group, pentylsulfinyl group,isopentylsulfinyl group, tert-pentylsulfinyl group, neopentylsulfinylgroup, 2-methylbutylsulfinyl group, 1,2-dimetylpropylsulfinyl group,1-ethylpropylsulfinyl group, hexylsulfinyl group, cyclopropylsulfinylgroup, cyclobutylsulfinyl group, cyclopentylsulfinyl group,cyclohexylsulfinyl group, cyclopropylmethylsulfinyl group,1-cyclopropylethylsulfinyl group, 2-cyclopropylethylsulfinyl group,cyclobutylmethylsulfinyl group, 2-cyclobutylethylsulfinyl group orcyclopentylmethylsulfinyl group.

[0082] Examples of the “lower alkylsulfonyl group” include amethylsulfonyl group, ethylsulfonyl group, propylsulfonyl group,isopropylsulfonyl group, butylsulfonyl group, isobutylsulfonyl group,sec-butylsulfonyl group, tert-butylsulfonyl group, pentylsulfonyl group,isopentylsulfonyl group, tert-pentylsulfonyl group, neopentylsulfonylgroup, 2-methylbutylsulfonyl group, 1,2-dimethylpropylsulfonyl group,1-ethylpropylsulfonyl group, hexylsulfonyl group, cyclopropylsulfonylgroup, cyclobutylsulfonyl group, cyclopentylsulfonyl group,cyclohexylsulfonyl group, cyclopropylmethylsulfonyl group,1-cyclopropylethylsulfonyl group, 2-cyclopropylethylsulfonyl group,cyclobutylmethylsulfonyl group, 2-cyclobutylethylsulfonyl group orcyclopentylmethlsulfonyl group.

[0083] The “sulfamoyl group unsubstituted or mono- or di-substituted bylower alkyl group” means a sulfamoyl group in which one or two hydrogenatom on the nitrogen atom in the sulfamoyl group may be substituted bysaid “lower alkyl group”. Examples of it include sulfamoyl group,methylsulfamoyl group, ethylsulfamoyl group, propylsulfamoyl group,isopropylsulfamoyl group, cyclopropylsulfamoyl group, butylsulfamoylgroup, isobutylsulfamoyl group, pentylsulfamoyl group,isopentylsulfamoyl group, hexylsulfamoyl group, isohexylsulfamoyl group,dimethylsulfamoyl group, diethylsulfamoyl group, dipropylsulfamoylgroup, disopropylsulfamoyl group, dibutylsulfamoyl group,dipentylsulfamoyl group, ethylmethylsulfamoyl group,metylpropylsulfamoyl group, ethylpropylsulfamoyl group,butylmethylsulfamoyl group, butylethylsulfamoyl group andbutylpropylsulfamoyl group.

[0084] Examples of the “alkylenedioxy group” include methylenedioxygroup or ethylenedioxy group.

[0085] The “lower alkenyloxy group” means a group in which one of thecarbon-carbon bonds in the lower C₃₋₆ alkoxy group is a double bond andthe position of which is not at the 1-position. Examples of it include2-propenyloxy group, 1-methyl-2-propenyloxy group,2-methyl-2-propenyloxy group, 1,1-dimethyl-2-propenyloxy group,1,2-dimethyl-2-propenyloxy group, 1,1,2-trimethyl-2-propenyloxy group,2-butenyloxy group, 1-methyl-2-butenyloxy group, 2-methyl-2-butenyloxygroup, 3-methyl-2-butenyloxy group, 3-butenyloxy group,1-metyl-3-butenyloxy group, 2-pentenyloxy group, 3-pentenyloxy group,4-pentenyloxy group, 2-cyclopentenyloxy group, 2-hexenyloxy group,3-hexenyloxy group, 4-hexenyloxy group, 5-hexenyloxy group,2-cyclohexenyloxy group or 3-cyclohexenyloxy group.

[0086] The “lower alkylene or alkylidene group” is C₁₋₆ alkylene or C₁₋₆alkylidene group, and includes methylene group, ethylene group,methylmethylene group, trimethylene group, dimethylmethylene group,tetramethylene group, methyltrimethylene group, ethylethylene group,dimethylethylene group, ethylmethylmethylene group, pentamethylenegroup, methyltetramethylene group, dimethyltrimethylene group,trimethylethylene group, dimethylmethylene group, hexamethylene group,methylpentamethylene group or dimethyltetramethylene group, and alsoincludes straight-chain or branched ones of these groups.

[0087] Examples of the protective group for the “unprotected orprotected hydroxyl group” described in the present specification includealkyl protective group such as a methyl group, tert-butyl group, benzylgroup, trityl group and methoxymethyl group; silyl protective group suchas trimethylsilyl group or tert-butyidimethylsilyl group; acylprotective group such as formyl group, acetyl group or benzoyl group;and carbonate protective group such as methoxycarbonyl group orbenzyloxycarbonyl group.

[0088] Examples of the protective group for the “unprotected orprotected carboxyl group” described in the present specification includealkylester protective groups such as a methyl group, ethyl group,tert-butyl group, benzyl group, diphenylmethyl group or trityl group;and silyl ester protective group such as trimethylsilyl group ortert-butyldimethylsilyl group.

[0089] Preferable embodiments in the definitions of the substituents ofthe compound according to the present invention are as follows.

[0090] The A is preferably phenyl group, naphthyl group, furyl group,thienyl group or pyridyl group, more preferably phenyl group or thienylgroup, and further preferably phenyl group.

[0091] Preferably, R¹ and R² each are hydrogen atom, fluorine atom,chlorine atom, bromine atom, trifluoromethyl group, cyano group,methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group,isopropoxycarbonyl group, dimethylamino group, trifluoroacetylaminogroup, hydroxyl group, methoxy group, isopropoxy group, methyl group,isopropyl group, trifluoromethoxy group, nitro group, phenyl group,phenoxy group, carboxyl group, carbamoyl group, dimethylcarbamoyl group,acetyl group, methylthio group, methylsulfinyl group, methylsulfonylgroup or sulfamoyl group, respectively, or R¹ and R² together formmethylenedioxy group. More preferably, R¹ and R² each are hydrogen atom,fluorine atom, chlorine atom, bromine atom, trifluoromethyl group, cyanogroup, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonylgroup, isopropoxycarbonyl group, trifluoroacetylamino group, methoxygroup, isopropoxy group, methyl group, isopropyl group, trifluoromethoxygroup, nitro group or methylthio group. Further preferably, R¹ and R²each are hydrogen atom, fluorine atom, chlorine atom, bromine atom,trifluoromethyl group, cyano group, methoxycarbonyl group,ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group ortrifluoromethoxy group.

[0092] As the combination of R¹ and R², it is preferable that R¹ ishydrogen atom, fluorine atom, chlorine atom, bromine atom,trifluoromethyl group, cyano group, methoxycarbony group, ethoxycarbonylgroup, propoxycarbonyl group, isopropoxycarbonyl group,trifluoroacetylamino group, methoxy group, isopropoxy group, methylgroup, isopropyl group, trifluoromethoxy group, nitro group ormethylthio group, and R² is hydrogen atom or fluorine atom. Morepreferably, R¹ is hydrogen atom, fluorine atom, chlorine atom, bromineatom, trifluoromethyl group, cyano group, methoxycarbonyl group,ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group ortrifluoromethoxy group, and R² is hydrogen atom or fluorine atom.

[0093] R³ is preferably hydrogen atom or methyl group, more preferablyhydrogen atom.

[0094] R⁴ is preferably hydrogen atom, methyl group, ethyl group,isopropyl group or acetyl group, more preferably methyl group, ethylgroup, isopropyl group or acetyl group, and further preferably methylgroup, ethyl group or isopropyl group.

[0095] R⁵ is preferably methoxy group, ethoxy group, propoxy group,isopropoxy group, butoxy group, isobutoxy group, cyclobutoxy group,cyclopropylmethyloxy group, 2-cyclopropylethyloxy group, pentyloxygroup, 3-pentyloxy group, isopentyloxy group, 2-methyl-2-butoxy group,cyclohexyloxy group, 3-butenyloxy group, 3-hydroxybutyloxy group,4-hydroxybutyloxy group, propyl group or phenoxy group; more preferably,ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxygroup, cyclobutoxy group, cyclopropylmethyloxy group,2-cyclopropylethyloxy group, pentyloxy group, 3-pentyloxy group,isopentyloxy group, 2-methyl-2-butoxy group or cyclohexyloxy group; andfurther preferably ethoxy group, propoxy group, isopropoxy group, butoxygroup or isobutoxy group.

[0096] R⁶ is preferably hydrogen atom, fluorine atom, hydroxyl group orhydroxymethyl group, more preferably hydrogen atom.

[0097] As the combination of R⁵ and R⁶, it is preferable that R⁵ isethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxygroup, cyclobutoxy group, cyclopropylmethyloxy group,2-cyclopropylethyloxy group, pentyloxy group, 3-pentyloxy group,isopentyloxy group, 2-methyl-2-butoxy group or cyclohexyloxy group, andR⁶ is hydrogen atom. More preferably, R⁵ is ethoxy group, propoxy group,isopropoxy group, butoxy group or isobutoxy group, and R⁶ is hydrogenatom.

[0098] It is preferable that the binding position of R⁵ is apara-position relative to —NR⁴—.

[0099] X is preferably a single bond, group: —CH(OH)—, oxygen atom orcarbonyl group, more preferably a single bond or group: —CH(OH)—, andfurther preferably a single bond.

[0100] Y is preferably methylene group, ethylene group, methylmethylenegroup, trimethylene group, benzylidene group or 4′-fluorobenzylidenegroup, more preferably methylene group, ethylene group, benzylidenegroup or 4′-fluorobenzylidene group, and further preferably methylenegroup, benzylidene group or 4′-fluorobenzylidene group.

[0101] Y is preferably forms an indanyl group when A is a phenyl groupand forms 5 or 6-membered rings together with X and carbon atoms on thebenzene ring.

[0102] Z is preferably a single bond or methylene group unsubstituted orsubstituted by methoxy group or hydroxyl group, and is more preferablymethylene group.

[0103] R⁷ and R⁸ each are preferably hydrogen atoms.

[0104] As the combination of the substituents, it is preferable that Ais a phenyl group, naphthyl group, furyl group, thienyl group or pyridylgroup each substituted by R¹ and R², wherein R¹ and R² each are hydrogenatom, fluorine atom, chlorine atom, bromine atom, trifluoromethyl group,cyano group, methoxycarbonyl group, ethoxycarbonyl group,propoxycarbonyl group, isopropoxycarbonyl group, dimethylamino group,trifluoroacetylamino group, hydroxyl group, methoxy group, isopropoxygroup, methyl group, isopropyl group, trifluoromethoxy group, nitrogroup, phenyl group, phenoxy group, carboxyl group, carbamoyl group,dimethylcarbamoyl group, acetyl group, methylthio group, methylsulfinylgroup, methylsulfonyl group or sulfamoyl group, or R¹ and R² togetherform methylenedioxy group; R³ is hydrogen atom or methyl group; R⁴ ishydrogen atom, methyl group, ethyl group, isopropyl group or acetylgroup; R⁵ is methoxy group, ethoxy group, propoxy group, isopropoxygroup, butoxy group, isobutoxy group, cyclobutoxy group,cyclopropylmethyloxy group, 2-cyclopropylethyloxy group, pentyloxygroup, 3-pentyloxy group, isopentyloxy group, 2-methyl-2-butoxy group,cyclohexyloxy group, 3-butenyloxy group, 3-hydroxybutyloxy group,4-hydroxybutyloxy group, propyl group or phenoxy group, and the bindingposition of R⁵ is at a para-position (4-position) relative to —NR⁴—; R⁶is hydrogen atom, fluorine atom, hydroxyl group or hydroxymethyl group;R⁷ is hydrogen atom; R⁸ is hydrogen atom; X is a single bond; Y ismethylene group, ethylene group, benzylidene group or4′-fluorobenzylidene group; and Z is a single bond or methylene groupunsubstituted or substitubed by methoxy group or hydroxyl group.

[0105] Further, it is preferable that A is phenyl group or thienyl groupeach substituted by R¹ and R²; R¹ and R² each are hydrogen atom,fluorine atom, chlorine atom, bromine atom, trifluoromethyl group, cyanogroup, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonylgroup, isopropoxycarbonyl group, dimethylamino group,trifluoroacetylamino group, hydroxyl group, methoxy group, isopropoxygroup, methyl group, isopropyl group, trifluoromethoxy group, nitrogroup, phenyl group, phenoxy group, carboxyl group, carbamoyl group,dimethylcarbamoyl group, acetyl group, methylthio group, methylsulfinylgroup, methylsulfonyl group or sulfamoyl group, or R¹ and R² togetherform methylenedioxy group; R³ is hydrogen atom or methyl group; R⁴ ismethyl group, ethyl group or isopropyl group; R⁵ is methoxy group,ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxygroup, cyclobutoxy group, cyclopropylmethyloxy group,2-cyclopropylethyloxy group, pentyloxy group, 3-pentyloxy group,isopentyloxy group, 2-methyl-2-butoxy group, cyclohexyloxy group,3-butenyloxy group, 3-hydroxybutyloxy group, 4-hydroxybutyloxy group,propyl group or phenoxy group; R⁶ is hydrogen atom, fluorine atom,hydroxyl group or hydroxymethyl group; R⁷ is hydrogen atom; R⁸ ishydrogen atom; X is a single bond, group: —CH(OH)—, oxygen atom orcarbonyl group; Y is methylene group, ethylene group, methylmethylenegroup, trimethylene group, benzylidene group or 4′-fluorobenzylidenegroup; Y may form indanyl group when A is phenyl group and forms 5- or6-membered rings together with X and carbon atoms on the benzene ring;and Z is a single bond or methylene group.

[0106] Further, it is preferable that A is phenyl group, naphthyl group,furyl group, thienyl group or pyridyl group each substituted by R¹ andR²; R¹ is hydrogen atom, fluorine atom, chlorine atom, bromine atom,trifluoromethyl group, cyano group, methoxycarbonyl group,ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group ortrifluoromethoxy group; R² is hydrogen atom or fluorine atom; R³ ishydrogen atom; R⁴ is hydrogen atom, methyl group, ethyl group, isopropylgroup or acetyl group; R⁵ is ethoxy group, propoxy group, isopropoxygroup, butoxy group, isobutoxy group, cyclobutoxy group,cyclopropylmethyloxy group, 2-cyclopropylethyloxy group, pentyloxygroup, 3-pentyloxy group, 3-methylbutoxy group, 2-methyl-2-butoxy groupor cyclohexyloxy group; R⁶ is hydrogen atom; R⁷ is hydrogen atom; R⁸ ishydrogen atom; X is a single bond, group: —CH(OH)—, oxygen atom orcarbonyl group; Y is a methylene group, benzylidene group or4′-fluorobenzylidene group; and Z is a single bond or methylene groupunsubstituted or substituted by methoxy group or hydroxyl group.

[0107] While the compounds according to the present invention arecompounds represented by the formula (I) or salts thereof, examples ofpreferable combinations of the substituents are as follows.

[0108] In the compounds represented by the formula (I) or salts thereof,A is phenyl group substituted by R¹ and R² or unsubstituted thienylgroup; R¹ is hydrogen atom, halogen atom, trifluoromethyl group, cyanogroup, lower alkoxycarbonyl group or trifluoromethoxy group; R² ishydrogen atom or halogen atom; R³ is hydrogen atom; R⁴ is methyl group;R⁵ is straight chain or branched C₂₋₄ alkoxy group, and the bindingposition of which is at a para-position (4-position) relative to —NR⁴—;R⁶ is hydrogen atom; R⁷ is hydrogen atom; R⁸ is hydrogen atom; X is asingle bond; Y is methylene group or benzylidene group substituted byR¹; and Z is methylene group. In this case, the formula (I) may be alsoexpressed as the formula (II):

[0109] (wherein A′ represents a phenyl group substituted by R¹ and R²,or unsubstituted thienyl group; —O(C₂₋₄ Alk) represents straight chainor branched C₂₋₄ alkoxy group; and Ya represents methylene group orbenzylidene group substituted by R¹).

[0110] Preferable examples of the compounds of the formula (I) include:

[0111]1-benzyl-4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]piperidin-4-ol;

[0112]1-benzyl-4-[2-[N-methyl-N-(4-n-propoxyphenyl)amino]ethyl]piperidin-4-ol;

[0113]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(4-chlorophenylmethyl)piperidin-4-ol;

[0114]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(4-(trifluoromethyl)phenylmethyl]piperidin-4-ol;

[0115]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(4-cyanophenylmethyl)piperidin-4-ol;

[0116]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(4-methoxycarbonylphenylmethyl)piperidin-4-ol;

[0117]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(3-fluorophenylmethyl)piperidin-4-ol;

[0118]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(3,4-diflorophenylmethyl)piperidin-4-ol;

[0119]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(4-fluorophenylmethyl)piperidin-4-ol;

[0120]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(2-fluorophenylmethyl)piperidin-4-ol;

[0121]1-(4-chlorophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol;

[0122]1-(4-bromophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol;

[0123]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-[4-(trifluoromethyl)phenylmethyl]piperidin-4-ol;

[0124]1-(4-fluorophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol;

[0125]1-(4-cyanophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol;

[0126]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-(4-nitrophenylmethyl)piperidin-4-ol;

[0127]1-[4-(methoxycarbonyl)phenylmethyl]-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol;

[0128]1-[4-fluoro-3-(trifluoromethyl)phenylmethyl]-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol;

[0129]1-(4-bromo-2-fluorophenylmethyl]-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol;

[0130]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-(2-thienylmethyl)piperidin-4-ol;

[0131]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-(3-thienylmethyl)piperidin-4-ol;

[0132]1-[2-(methoxycarbonyl)phenylmethyl]-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol;

[0133]1-[3-(methoxycarbonyl)phenylmethyl]-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol;

[0134]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-[4-(isopropoxycarbonyl)phenylmethyl]piperidin-4-ol;

[0135]1-[2-fluoro-4-(trifluoromethyl)phenylmethyl]-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol;

[0136]4-[2-[N-methyl-N-(4-ethoxyphenyl)amino]ethyl]-1-[4-(trifluoromethyl)phenylmethyl]piperidin-4-ol;

[0137]1-diphenylmethyl-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol;

[0138]1-bis(4-fluorophenyl)methyl-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol;and

[0139]1-diphenylmethyl-4-[2-[N-(4-ethoxyphenyl)-N-methylamino]ethyl]piperidin-4-ol.

[0140] These compounds can form salts to be described hereinafter.

[0141] The compounds according to the present invention may containasymmetric carbon atoms, and the present invention contains mixtures ofall of optically active or inactive stereoisomers (such as enantiomersand diastereomers), geometrical isomers and tautomers, and isolatedcompounds thereof. The isolation and purification of the stereoisomerscan be made by those skilled in the art by optical resolution usingpreferential crystallization and column chromatography or by asymmetricsynthesis.

[0142] The compound (I) according to the present invention may form anacid addition salt. A salt with a base may be also formed depending onthe kind of the substituent. The salt is not particularly restricted solong as it is pharmaceutically acceptable. Examples of the salt includeacid addition salts with an inorganic acid such as hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid orphosphoric acid; acid addition salts with an organic carboxylic acidsuch as acetic acid, propionic acid, oxalic acid, malonic acid, succinicacid, fumaric acid, maleic acid, lactic acid, formic acid, malic acid,tartaric acid, citric acid or mandelic acid; acid addition salts with anorganic sulfonic acid such as methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid or 2-hydroxyethanesulfonicacid; an acid addition salt with an acidic amino acid such as asparticacid and glutamic acid; a salt with an alkali metal or alkaline earthmetal such as sodium, potassium, magnesium, calcium or aluminum; a saltwith an organic base such as methylamine, ethylamine, ethanolamine,pyridine, lysine, arginine or ornithine; or an ammonium salt. Thesesalts can be formed by conventional methods, for example, mixing of anequivalent compound of the present invention with a solution containinga desired acid or base, and collecting the desired salt by filtration orevaporation of solvents. The compounds of the present invention or saltsthereof may form a solvate with a solvent such as water, ethanol orglycerol.

[0143] The salts of the compounds of the present invention may containmono-, di- or tri-salts. The compounds of the present invention maysimultaneously form both acid addition salt and salt with a basedepending on the substituent on the side chains of the compounds.

[0144] Further, the present invention contains hydrates, variouspharmaceutically acceptable solvates and polymorphic crystals of thecompound (I) may be included in the present invention. Naturally, thepresent invention is not restricted to the compounds to be describedhereinafter and contains all the compound represented by the formula (I)or pharmaceutically acceptable salts thereof.

[0145] The manufacturing methods according to the present invention willbe described hereinafter together with reaction processes thereof.Definitions of A, R³, R⁴, R⁴′, R⁵, R⁵′, R⁶, R⁶′, R⁷, R⁸, W, P, Q, X, Y,Y′, Z and Z′ in the compounds represented by the formulae (I), (I)-a,(I)-b, (VI), (VI′), (VII′), (VIII), (IX), (X), (X′), (XI), (XII) and(XIII) on the reaction schemes and descriptions in the MANUFACTURINGMETHODs 1, 2, 3 and 4 have the same meanings as defined above, unlessotherwise stated.

[0146] The compounds represented by the formula (I) according to thepresent invention and salts thereof can be manufactured from thecompounds represented by the formula (III) (in which R⁴′, R⁵′ and R⁶′have the same meanings as defined above), formula (III′) (in which R⁴′,R⁵ and R⁶ have the same meanings as defined above), formula (IV) (inwhich A, R³, X, Y′ and Z have the same meanings as defined above),formula (V) (in which R³, P and Z have the same meanings as definedabove), formula (XI), formula (XII), formula (XIII), formula (XIV) (inwhich A, R³, R⁷, X, Y′ and Z have the same meanings as defined above),formula (XV) (in which R³, R⁷, P and Z have the same meanings as definedabove), formula (XVIII) (in which A, R⁷, R⁸, X and Y′ have the samemeanings as defined above) and formula (XIX) (in which R⁷, R⁸ and P havethe same meanings as defined above), which may be synthesized startingfrom the compounds known in the art or from commertially availablecompounds, by each method of the MANUFACTURING METHODs 1, 2, 3 and 4, orby modifications thereof. The starting materials, intermediate productsand final products may be manipulated as salts, according to thenecessity.

[0147] The manufacturing methods will be described in detailhereinafter.

[0148] MANUFACTURING METHOD 1

[0149] The compounds which R⁷ and R⁸ in the formula (I) representhydrogen atom are represented by the formula (I)-a, and themanufacturing method thereof is shown below.

[0150] The compound represented by the formula (I)-a and the saltthereof can be manufactured from the compound represented by theformulae (III) and (IV), or (III) and (V) according to the processes inthe reaction scheme I

[0151] Process 1

[0152] The compound represented by the formula (VI) can be produced byreacting the compound represented by the formula (III) with the compoundrepresented by the formula (IV) using a condensation agent such as1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (watersoluble carbodiimide hydrochloride, WSC.HCl) or dicyclohexylcarbodiimide(DCC) in a solvent that does not take part in the reaction, e.g., ahalogenated hydrocarbon solvent such as methylene chloride andchloroform, an ether solvent such as diethyl ether and tetrahydrofuran,a hydrocarbon solvent such as benzene and hexane, or a polar solventsuch as dimethylformamide and dimethylsulfoxide in a temperature rangeof 0° C. to a reflux temperature of the reaction mixture.

[0153] This reaction may proceed using a dehydrating agent such asphosphorus oxychloride in the solvent that does not take part in thereaction including the halogenated hydrocarbon solvent such as methylenechloride and chloroform, ether solvent such as diethyl ether andtetrahydrofuran or the hydrocarbon solvent such as benzene and hexane ina temperature range of −20° C. to a reflux temperature of the reactionmixture in the presence of a base such as pyridine and triethylamine.

[0154] The compound represented by the formula (VI) can be also producedby converting the compound represented by the formula (IV) into an acidchloride using thionyl chloride and by reacting the acid chlorideobtained with the compound represented by the formula (III) in thepresence of an organic base such as triethylamine and pyridine or aninorganic base such as potassium carbonate in the halogenatedhydrocarbon solvent such as methylene chloride and chloroform, ethersolvent such as diethyl ether and tetrahydrofuran or hydrocarbon solventsuch as benzene and hexane, or in a basic solvent such as pyridine andtriethylamine in a temperature range of −20° C. to a reflux temperatureof the reaction mixture.

[0155] The compound represented by the formula (VI) may be alsomanufactured according to the <Process 2>, <Process 3> and <Process 4>to be described hereinafter.

[0156] Process 2

[0157] The compound represented by the formula (VII) (in which R³, R⁴,R⁵′, R⁶′, P and Z have the same meaning as defined above) can bemanufactured from the compound represented by the formula (III) and thecompound represented by the formula (V) in accordance with the method inthe <Process 1>. As the protective group P, an appropriate protectivegroup described in the general remarks of “Protective Groups in OrganicSynthesis, 3rd edition, edited by T. W. Green and P. G. M. Wuts,published by John Wiley and Sons, 1999” may be used. Such protectivegroup includes an alkyl protective group such as a benzyl group, tritylgroup and methoxymethyl group, and a carbamate protective group such asa tert-butoxycarbonyl group and benzyloxycarbonyl group.

[0158] Process 3

[0159] The compound represented by the formula (VIII) can be produced byde-protection of the position 1 of piperidine ring of the compoundrepresented by the formula (VII).

[0160] The position 1 of piperidine ring of the compound represented bythe formula (VII) can be de-protected in accordance with the methoddescribed in the general remarks of “Protective Groups in OrganicSynthesis, 3rd edition, 1999”. The compound represented by the formula(VIII) can be produced by a de-protection reaction using a catalyst suchas palladium on carbon or platinum oxide in an alcoholic solvent such asmethanol and ethanol, or a solvent such as ethyl acetate, acetic acidand water under hydrogen atmosphere or in the presence of ammoniumformate in a temperature range from 0° C. to a reflux temperature of thereaction mixture, when the protective group (P in the formula) is, forexample, benzyl group or benzyloxycarbonyl group. Alternatively, thecompound represented by the formula (VIII) can be produced by ade-protection reaction using an acid such as trifluoroacetic acid orhydrochloric acid in the presence or absence of anisole in a temperaturerange from 0° C. to a reflux temperature of the reaction mixture, whenthe protective group (P in the formula) is, for example,tert-butoxycarbonyl group.

[0161] Process 4

[0162] The compound represented by the formula (VIII) can be reactedwith the compound represented by the formula (IX) by the followingmethods depending on the kind of —Y′ and -Q.

[0163] (Method A): The compound represented by the formula (VI) can beproduced by reacting the compound represented by the formula (VIII) withthe compound represented by the formula (IX) in the presence or absenceof the organic base such as triethylamine and pyridine or inorganic basesuch as potassium carbonate in a solvent that does not take part in thereaction, e.g., the halogenated hydrocarbon solvent such as methylenechloride and chloroform, ether solvent such as diethyl ether andtetrahydrofuran, hydrocarbon solvent such as benzene and hexane, orpolar solvent such as dimethylformamide and dimethylsulfoxide in atemperature range from 0° C. to a reflux temperature of the reactionmixture, when —Y′ and -Q together represent halogenated alkyl. Sodiumiodide may be used as a catalyst thereat.

[0164] (Method B): The compound represented by the formula (VI) can beproduced by reacting the compound represented by the formula (VIII) withthe compound represented by the formula (IX) using an appropriatereducing agent in the presence or absence of the acid catalyst such asacetic acid in a solvent, e.g., aromatic hydrocarbon solvent such asbenzene and toluene, halogenated hydrocarbon solvent such as methylenechloride and chloroform, or alcoholic solvent such as methanol andethanol, when —Y′ and -Q together represent aldehyde or ketone. Whileany reducing agents capable of reducing an imino group into an aminogroup may be generally used, sodium triacetoxyborohydride, sodiumborohydride, lithium borohydride, diisobutylaluminum hydride and sodiumcyanoborohydride are preferable among the reducing agents. The reducingreaction can be conducted in the temperature range from −78° C. to roomtemperature, preferably at room temperature and for the enough time toproceed the reaction sufficiently, concretely from 3 to 12 hours.

[0165] (Method C): The compound represented by the formula (VI) can beproduced in accordance with the method in the <Process 1>, when —Y′ and-Q together represent carboxylic acid.

[0166] Process 5

[0167] The compound represented by the formula (I)-a or a salt thereofcan be manufactured by reacting the compound represented by the formula(VI) using a reducing agent such as lithium aluminum hydride,diisobutylaluminum hydride, and a borane complex represented byborane-methyl sulfide complex and borane-tetrahydrofuran complex in asolvent that does not take part in the reaction, e.g., ether solventsuch as diethyl ether and tetrahydrofuran or an aromatic hydrocarbonsolvent such as toluene and benzene in a temperature range from 0° C. toa reflux temperature of the reaction mixture.

[0168] When Y′ represents an alkylenecarbonyl group or carbonyl group inthe compound represented by the formula (VI), Y′ is simultaneouslyreduced under the reaction condition employed to afford a compound inwhich Y is corresponding lower alkylene group.

[0169] When R⁵ or R⁶′ represent lower alkoxycarbonyl groups, the estergroup is reduced simultaneously with the reduction of the amide bondingto be converted to a corresponding alcoholic group. The reduction canproceed by the same method after hydrolyzing the ester group to thecarboxyl group. Methods known in the art, for example treating thecompound in an alcoholic solvent such as methanol and ethanol in thepresence of an aqueous lithium hydroxide or sodium hydroxide at atemperature from room temperature to a reflux temperature of thereaction mixture, may be used for hydrolysis.

[0170] The compound represented by the formula (I)-a or a salt thereofcan be also produced using the compound represented by the formula(VIII) through the <Process 6> and <Process 7> shown below.

[0171] Process 6

[0172] The compound represented by the formula (X) can be produced fromthe compound represented by the formula (VIII) according to the methodin the <Process 5>.

[0173] The compound represented by the formula (X) can be also producedby reducing the compound represented by the formula (VII) in accordancewith the method in the <Process 5>, followed by de-protection of theposition 1 of piperidine ring of the obtained compound in accordancewith the method in the <Process 3>.

[0174] Process 7

[0175] The compound represented by the formula (I)-a or a salt thereofcan be produced from the compounds represented by the formulae (X) and(IX). The compound represented by the formula (I)-a can be produced bythe Methods A or B in the <Process 4> when —Y′ and -Q together representhalogenated alkyl group, aldehyde or ketone. When —Y′ and -Q togetherrepresent carboxylic acid, the compound can also be produced by reducingan amide bonding subsequently produced from the method of the Method Cin the <Process 4> in accordance with the method of the <Process 5>.

[0176] MANUFACTURING METHOD 2

[0177] The method for manufacturing the compound represented by theformula (I)-b is described hereinafter, wherein R⁷ and R⁸ representhydrogen atoms and Z is denoted by Z′ in the compound represented by theformula (I).

[0178] The compound represented by the formula (I)-b or a salt thereofcan be manufactured from the compound represented by the formulae (XI)and (XII), or (XI) and (XIII) according to each manufacturing process inthe Reaction Scheme 2.

[0179] Process 1

[0180] The compound represented by the formula (VI′) can be produced byan addition reaction between the compound represented by the formula(XI) and the compound represented by the formula (XII), followed byalkylation of the hydroxyl group produced according to the necessity.When W is hydrogen atom in the compound represented by the formula (XI),the addition reaction is performed by reacting the compound representedby the formula (XI) with a metal amide reagent such as lithiumdiisopropylamide, lithium hexamethyldisilazide and potassiumhexamethyldisilazide, or an organometallic reagent represented by tin(II) trifulate to form a metal enolate in a solvent that does not takepart in the reaction, e.g., an ether solvent such as diethyl ether andtetrahydrofuran or a hydrocarbon solvent such as benzene and hexane in atemperature range from −100° C. to room temperature, followed byreacting the reaction product with the compound represented by theformula (XII) in a temperature range from −100° C. to room temperature.

[0181] When W is halogen atom, preferably bromine atom, in the compoundsrepresented by the formula (XI), the addition reaction is performed byreacting the compound represented by the formula (XI) with zinc powderto form a zinc compound in a solvent that does not take part in thereaction including an ether solvent such as diethyl ether andtetrahydrofuran or a hydrocarbon solvent such as benzene and hexane,followed by reacting the reaction product with the compound representedby the formula (XII).

[0182] Alkylation of the tertiary hydroxyl group produced by theaddition reaction can be performed using an alkylating agent such as analkyl halide represented by methyl iodide or an alkyl sulfaterepresented by dimethyl sulfate in the presence of a base such as sodiumhydride in a solvent that does not take part in the reaction such asdimethylformamide or dimethylimidazolidone in a temperature range from−20° C. to a reflux temperature of the reaction mixture, preferably in atemperature range from an ice-cooled temperature to room temperature.

[0183] The compound represented by the formula (VI′) can be alsoproduced by the methods in the <Process 2>, <Process 3> and <Process 4>to be described hereinafter.

[0184] Process 2

[0185] The compound represented by the formula (VII′) can be producedfrom the compounds represented by the formulae (XI) and (XIII) inaccordance with the methods in the <Process 1>.

[0186] Process 3

[0187] The compound represented by the formula (VIII′)(in which R³, R⁴,R⁵, R⁶ and Z′ have the same meanings as defined above) can be producedfrom the compounds represented by the formula (VII′) in accordance withthe <Process 3> in the MANUFACTURING METHOD 1.

[0188] Process 4

[0189] The compound represented by the formula (VI′) can be producedfrom the compounds represented by the formulae (VIII′) and (IX) inaccordance with the <Process 4> in the MANUFACTURING METHOD 1.

[0190] Process 5

[0191] The compound represented by the formula (I)-b or a salt thereofcan be produced from the compound represented by the formula (VI′) inaccordance with the <Process 5> in the MANUFACTURING METHOD 1.

[0192] The compound represented by the formula (I)-b or a salt thereofcan be also produced from the compound represented by the formula(VIII′) in accordance with the <Process 6> and <Process 7> to bedescribed hereinafter.

[0193] Process 6

[0194] The compound represented by the formula (X′) can be also producedfrom the compound represented by the formula (VIII′) in accordance withthe method in the <Process 5>.

[0195] The compound represented by the formula (X′) is also produced byreducing the compound represented by the formula (VII′) in accordancewith the method in the <Process 5>, followed by de-protection of theposition 1 of piperidine ring in accordance with the method in the<Process 3>.

[0196] Process 7

[0197] The compound represented by the formula (I)-b or a salt thereofcan be produced from the compounds represented by the formulae (X′) and(IX) in accordance with the method in the <Process 7> in theMANUFACTURING METHOD 1.

[0198] MANUFACTURING METHOD 3

[0199] The method for manufacturing the compound represented by theformula (I)-c is described hereinafter, wherein R⁸ in the formula (I)represents hydrogen atom.

[0200] The compound represented by the formula (I)-c (in which A, R³,R⁴, R⁵, R⁶, R⁷, X, Y and Z have the same meanings as defined above) or asalt thereof can be produced from the compounds represented by theformulae (III′) and (XIV), or (III′) and (XV) in accordance with eachmanufacturing process in the Reaction Scheme 3.

[0201] Process 1

[0202] The compound represented by the formula (I)-c or a salt thereofcan be produced from the compounds represented by the formulae (III′)and (XIV) in accordance with the Method B described in the <Process 4>of the MANUFACTURING METHOD 1.

[0203] The compound represented by the formula (I)-c can be produced bysubsequently reducing the amide bonding in accordance with the method inthe <Process 5> of the MANUFACTURING METHOD 1, when Y′ representsalkylenecarbonyl group or carbonyl group.

[0204] The compound represented by the formula (I)-c or a salt thereofcan be also produced in accordance with the <Process 2>, <Process 3> and<Process 4> to be described below.

[0205] Process 2

[0206] The compound represented by the formula (XVI) (in which R³, R⁴,R⁵, R⁶, R⁷, P and Z have the same meanings as defined above) can beproduced from the compounds represented by the formulae (III′) and (XV)in accordance with the method in the <Process 1>.

[0207] Process 3

[0208] The compound represented by the formula (XVII) (in which R³, R⁴,R⁵, R⁶, R⁷ and Z have the same meanings as defined above) can beproduced from the compound represented by the formula (XVI) inaccordance with the method in the <Process 3> in the MANUFACTURINGMETHOD 1.

[0209] Process 4

[0210] The compound represented by the formula (I)-c or a salt thereofcan be produced from the compounds represented by the formulae (XVII)and (IX) in accordance with the method in the <Process 7> in theMANUFACTURING METHOD 1.

[0211] MANUFACTURING METHOD 4

[0212] The compound which Z in the formula (I) represents a single bondis represented by the formula (I)-d, and the method for manufacturingthereof will be described hereinafter.

[0213] The compound represented by the formula (I)-d (in which A, R³,R⁴, R⁵, R⁶, R⁷, R⁸, X and Y have the same meaning as defined above) anda salt thereof can be produced from the compounds represented by theformulae (III′) and (XVIII), or (III′) and (XIX) in accordance with themanufacturing processes in the Reaction Scheme 4.

[0214] Process 1

[0215] The compound represented by the formula (I)-d or a salt thereofcan be produced by reacting the compound represented by the formula(III′) with the compound represented by the formula (XVIII) in thepresence of an acid catalyst or a base catalyst in a solvent that doesnot take part in the reaction, e.g., halogenated hydrocarbon solventsuch as methylene chloride and chloroform, an ether solvent such asdiethyl ether and tetrahydrofuran, a hydrocarbon solvent such as benzeneand hexane, or a polar solvent such as dimethylformamide anddimethylsulfoxide in a temperature range from 0° C. to a refluxtemperature of the reaction mixture. The compound may be also producedby a reaction in accordance with the method described by Gary H. Posneret al, in Journal of the American Chemical Society, Vol. 99,pp8208-8214, 1977 in diethyl ether in the presence of neutral alumina atroom temperature.

[0216] The compound represented by the formula (I)-d can be produced bysucceeding reduction of the amide bonding in accordance with the methodin the <Process 5> in the MANUFACTURING METHOD 1 when Y′ represents analkylenecarbonyl group or a carbonyl group.

[0217] The compound represented by the formula (I)-d or a salt thereofcan be also produced in accordance with the <Process 2>, <Process 3> and<Process 4> to be described hereinafter.

[0218] Process 2

[0219] The compound represented by the formula (XX) (in which R³, R⁴,R⁵, R⁶, R⁷, R⁸ and P have the same meanings as defined above) can beproduced from the compounds represented by the formulae (III′) and (XIX)in accordance with the method in the <Process 1>.

[0220] Process 3

[0221] The compound represented by the formula (XXI) (in which R³, R⁴,R⁵, R⁶, R⁷ and R⁸ represent the same meanings as hitherto described) canbe produced from the compound represented by the formula (XX) inaccordance with the method in the <Process 3> in the MANUFACTURINGMETHOD 1.

[0222] Process 4

[0223] The compound represented by the formula (I)-d and a salt thereofcan be produced from the compounds represented by the formulae (XXI) and(IX) in accordance with the method in the <Process 7> in theMANUFACTURING METHOD 1.

[0224] The compound synthesized in each manufacturing method above canbe converted in each process of each manufacturing process according tothe method to be described hereinafter.

[0225] Among the compounds represented by the formulae (I)-a, (I)-b,(I)-c, (I)-d, (XVI) and (XX), the compounds in which R⁴ representshydrogen atom can be converted to compounds in which R⁴ is lower alkylgroup using an alkylating agent such as an alkyl halide represented bymethyl iodide, or an alkyl sulfate represented by dimethyl sulfate in asolvent that does not take part in the reaction, e.g., a halogenatedhydrocarbon solvent such as methylene chloride and chloroform, an ethersolvent such as diethyl ether and tetrahydrofuran, a hydrocarbon solventsuch as benzene and hexane, or a polar solvent such as dimethylformamideand dimethylsulfoxide in the presence of an inorganic base such aspotassium hydroxide, sodium hydride and potassium carbonate or anorganic base such as triethylamine and pyridine in a temperature rangefrom 0° C. to a reflux temperature of the reaction mixture. Thecompounds can also be converted to compounds in which R⁴ represents alower alkyl group using aldehyde derivative or ketone derivative byconducting reaction in accordance with the Method B described in the<Process 4> in the MANUFACTURING METHOD 1. By an acylation reaction inaccordance with the method described in the <Process 1> in theMANUFACTURING METHOD 1, the compounds may be also converted to compoundsin which R⁴ represents a lower alkanoyl group using a carboxylic acidderivative. At that time, the compounds obtained by the process abovemay be converted to the compounds in which R⁴ represents a lower alkylgroup by subsequently applying a reduction treatment described in the<Process 5> in the MANUFACTURING METHOD 1.

[0226] Among the compounds represented by the formulae (VI), (VII),(VI′) and (VII′), compounds in which R⁴′ is hydrogen atom can bealkylated to be converted to compounds in which R⁴′ is lower alkyl groupusing an alkylating agent such as an alkyl halide represented by methyliodide or an alkyl sulfate represented by dimethyl sulfate in thepresence of a base such as potassium hydroxide and sodium hydride in asolvent that does not take part in the reaction including a halogenatedhydrocarbon solvent such as methylene chloride and chloroform, an ethersolvent such as diethyl ether and tetrahydrofuran, a hydrocarbon solventsuch as benzene and hexane, or a polar solvent such as dimethylformamideand dimethylsulfoxide in a temperature range from 0° C. to a refluxtemperature of the reaction mixture.

[0227] Among the compounds represented by the formulae (I)-a, (I)-b,(I)-c, (I)-d, (VI), (VII), (VI′), (VII′), (XVI) and (XX), compoundswhich contain alkoxy group on the benzene ring as a substituent can beconverted, after de-alkylation using boron tribromide or hydrobromicacid-acetic acid, etc., to other alkoxy substituted form in the presenceof a base such as sodium hydride using the alkylating agents describedabove in a solvent that does not take part in the reaction such asdimethylformamide and dimethylimidazolidone in a temperature range from−20° C. to a reflux temperature of the reaction mixture, preferably froman ice-cooled temperature to room temperature. At that time, thecompounds may be also converted to lower alkoxy compounds substituted byhydroxyl groups by reducing with lithium aluminum hydride, sodiumborohydride or the like, after alkylation with an alkyl halide havingoxygen functional group represented by bromoacetic acid ester orbromoacetone as an alkylation agent.

[0228] Among each compound produced by each method described above,compounds which X represents carbonyl group can be converted to group:—CH(OH)— by reacting the compounds in a temperature range from 0° C. toa reflux temperature of the reaction mixture in an alcoholic solventsuch as methanol and ethanol using a reducing agent such as sodiumborohydride according to the necessity.

[0229] Among each compound produced each method described above,compound which contain lower alkoxycarbonyl group as a substituent canbe converted to a carboxyl group by conventional methods, for example,by hydrolysis in the presence of an aqueous alkali solution such asaqueous solution of lithium hydroxide or sodium hydroxide in analcoholic solvent such as methanol and ethanol in a temperature rangefrom room temperature to a reflux temperature of the reaction mixture.The obtained carboxyl group can be converted to a carbamoyl group thatmay be unsubstituted or mono- or di-substituted by lower alkyl groups bya condensation reaction in accordance with the method described in theMethod C.

[0230] Among the compounds manufactured by the methods as hithertodescribed, compounds which contain halogen atoms, preferably bromineatoms, as substituents on the aromatic ring, the bromine atom can beconverted to cyano group by conventional methods, for example, byreacting the compound using copper (I) cyanate or potassium cyanate in asolvent that does not take part in the reaction, e.g., a polar aproticsolvent such as dimethylformamide, dimethylsulfoxide anddimethylimidazolidone in a temperature range from room temperature to areflux temperature of the reaction mixture. In this reaction, transitionmetal complexes such as a palladium complex represented by palladiumacetate and nickel complex represented by tetrakistriphenylphosphinenickel may be used as catalysts. The cyano group can be furtherconverted to lower alkanoyl group by reacting the compound with anorganometallic compound represented by alkyl magnesium bromide and alkyllithium in a solvent that does not take part in the reaction includingether solvents such as diethyl ether and tetrahydrofuran in atemperature range from −100° C. to room temperature.

[0231] When the compounds manufactured in each manufacturing method ashitherto described contain reactive groups such as hydroxyl group, aminogroup and carboxyl group, these substituents can be appropriatelyprotected in each manufacturing process, and the protective groups canbe removed at an appropriate reaction process. While these protectivegroups may be appropriately introduced and eliminated depending on thetype of the protected group or protection group, the methods availableare described, for example, in Protective Groups in Organic Synthesis,3rd edition, 1999.

[0232] Among the intermediate compounds to be used in each manufacturingprocess, the compound represented by the formula (XII) may be producedin accordance with the method known in the art. For example, thecompound can be produced by reacting 4-piperidone or its equivalencewith the compound represented by the formula (IX) in accordance with themethod described in the <Process 4> in the MANUFACTURING METHOD 1.Alternatively, Compound represented by the formula (XII) in which Y′representes Y can be produced from the compound represented by thefollowing formula (XXII) in accordance with a reaction described byHuegi et al., in Journal of Med. Chem., Vol. 26, p42, 1983:

[0233] (wherein A, X and Y have the same meanings as defined above.)

[0234] The compounds represented by the formulae (IV) and (V) can beproduced by reacting the compounds represented by the formulae (XII) and(XIII) with unprotected or protected acetic acid having a desiredsubstituent in accordance with the method described in the MANUFACTURINGMETHOD 2.

EXPERIMENTAL EXAMPLES

[0235] While the present invention is described with reference to theexamples, the present invention is by no means restricted to theseexamples.

Experimental Example 1

[0236] Suppression Activity of Veratrine-Induced Contracture of IsolatedCardiac Muscle

[0237] Rats were anesthetized with 40 mg/kg (i.p.) of pentobarbitalsodium and held in supine postion, and heparin was injected through thejugular vein. After starting artificial respiration under a condition of20 mL/kg and 54 strokes/min, the chest was open between the second andthirdcostae. A polyethylene tube filled with Krebs-Ringer-HEPES (KRH)solution (pH 7.4) containing 1 mM CaCl₂ was inserted through the aortain retrograde manner, and the tube was fixed. The heart was extractedsimultaneously with perfusion of the KRH solution at a hydraulicpressure of 70 cm water column. After thoroughly flushing the remainingblood by spontaneous contraction of the heart, stroke of the heart washalted by perfusion of the Ca²⁺ free KRH solution for 10 minutes. Theperfusion solutions described above were used after oxygenation with amixed gas containing 95% O₂ and 5% CO₂ and keeping at a temperature of37° C. Then, a KRH solution containing 25 μM CaCl₂, 0.06% collagenaseand 0.1% albumin was perfused for 20 minutes at 37° C. until the heartwas soften. The ventricles were cut into pieces in the collagenasesolution at 37° C., followed by an enzyme treatment for 10 minutes whileaerating the solution with the mixed gas of 95% O₂/5% CO₂. The cellswere dispersed by pipetting, and connective tissues were removed fromthe dispersed cells by filtering with a stainless steel mesh. Afterhalting the enzyme reaction by adding albumin in the filtrate, thesupernatant was discarded by centrifugation. The cells were suspended inthe KRH solution containing 25 μM CaCl₂ and 1% albumin, and the Ca²⁺concentration was increased stepwise by sequentially adding the CaCl₂solution in the suspension to a final concentration of 0.5 mM. A pelletof the cells was obtained by centrifugation after allowing thesuspension to stand for 10 minutes. The pellet of the cells was laid ona column (10 cm in height and 15 mm in diameter) filled with the KRHsolution containing 1 mM CaCl₂ and 2% albumin, and the column wasallowed to stand for 5 to 10 minutes. The supernatant was gentlyremoved, and the number of rod-shaped cells in the precipitated cellswas counted. The cells were re-suspended in the KRH solution containing1 mM CaCl₂ and 0.1% albumin, and pipetted into each well of a 48 wellmulti-plate (3548, COSTER) coated with poly-L-lysine so that each wellcontains 0.5 mL of the cell suspension with 1×10⁴ cells/well. Thesuspension in each well was aerated with a mixed gas of 95% O₂/5% CO₂ at37° C. for 1 hour to allow the cells to adhere on the bottom of thewell. The solution in the well was flushed with a KRH solutioncontaining 0.025% lactic acid and 1 mM CaCl₂ to remove the cells thatdid not adhere on the bottom. Then, the medium was replaced with a KRHsolution containing a test compound, 0.025% lactic acid and 1 mM CaCl₂,followed by aerating with a mixed gas containing 95% O₂/5% CO₂ at 37° C.for 30 minutes. After taking a photograph under a microscope, a KRHsolution containing veratrine, 0.025% lactic acid and 1 mM CaCl₂ wasadded to each well so that the final concentration of veratrin becomes100 gg/mL, followed by taking a photograph of morphological changes ofthe cells after 5 minutes passed from the addition. A change from therod-shape cell to a spherical cell was defined as contraction byveratrine. Veratrine in this concentration can contract all the cells.The concentration of the test compound when half of the cells werecontracted was defined as IC₅₀ (μmol/L) that can be calculated by aprobit analysis. The results are shown in Table 1. TABLE 1 SuppressionActivity of Veratrine-induced Contracture of Isolated Cardiac MuscleExample No. IC₅₀ (μmol/L) 146 1.2 176 0.9 183 1.0 210 0.9 220 0.7 2210.3 236 0.3 240 0.7 278 0.3

[0238] The results above show that the compounds according to thepresent invention have remarkable suppressive effects on contracture ofthe isolated cardiac muscle cells caused by veratrine.

Experimental Example 2

[0239] Suppression Effect on Ischemia-Reperfusion Induced Arrythmia inRats

[0240] The test compounds were administered to rats starved from a daybefore by gavage at a dosage of 10 mL/kg under an awaken condition. Therats were anesthetized with 60 mg/kg (i.p.) of sodium pentobarbitalafter 35 minutes passed from the administration, and were fixed on awarmed sheet in supine position. The body temperature was kept at 37° C.during the experiment, and artificial respiration was started under acondition of 15 mL/Kg and 55 strokes/minutes. A polyethylene tube formeasuring the blood pressure filled with a heparin-physiological salinesolution was inserted into the left common carotid artery at a depth of2 cm and fixed. Then, the left chest was open, and the left majorcoronary artery at an atrium side was sewed using a needle with a threadin order to ligate the coronary artery. After stabilizing for about 10minutes (after 60 minutes passed from the administration), the coronaryartery was ligated for 5 minutes, and re-perfused for 10 minutesthereafter. The ligation of the coronary artery was conducted byinserting a suture through a snare made of a polyethylene tube andpulling the both ends of the suture, followed by pressing the snare ontothe heart. The re-perfusion was conducted by removing the snare. Theaortic blood pressure was measured with a pressure transducer. Anelectrocardiogram was led by a standard lead II. The heart rate wasmeasured using the R-R interval on the electrocardiogram or from theblood pressure using a tachometer. Each signals were recorded with achart recorder with verification on a monitor, while simultaneouslyrecording on a magnetic medium using a personal computer. After thecompletion of the experiments, generation of ventricular fibrillationwas confirmed for each individual using an analysis software running onthe personal computer, and incidence (%) of the ventricular fibrillationwas determined for each administration group. The results are shown inTables 2-1 and 2-2. TABLE 2-1 Effectiveness (1) in Ischemia-ReperfusionInduced Arrythmia Model in Rats Number Example Dosage of Incidence (%)of the No. (mg/kg) animals ventricular fibrillation solvent — 11 63.6146 5 10 30.0 146 10 9 11.1 146 20 9 0.0

[0241] TABLE 2-2 Effectiveness (2) in Ischemia-Reperfusion InducedArrythmia Model of Rat Number Example Dosage of Incidence (%) of the No.(mg/kg) animals ventricular fibrillation solvent — 7 57.1 233 5 7 28.6240 5 7 0.0 278 5 8 0.0

[0242] The compounds according to the present invention were shown tosuppress the incidence (%) of the ventricular fibrillation in thisexample.

Experimental Example 3

[0243] Suppressive Action on Arrythmia Induced by Two Step Ligation ofCanine Coronary Artery

[0244] After anesthetizing with 30 mg/kg (i.v.) of thiopental sodium, abeagle dog was ventilated by artificial respiration under a condition of20 mL/kg and 22 strokes/min. The fifth left intercostal space was openedunder sterile condition to incise membrana pericardiac cavity, and theheart was hanged in the thoracic cavity. The left anteirior descendinglimb of the coronary artery was peeled at 1 cm downstream of the jointto the circumflexus branch, and the artery was wound with two strings ofsutures. Blood vessel of the artery was at first ligated together with a19G needle with a round tip, and the constriction is prepared by pullingout the needle (one step ligation). Thirty minutes after the firstligation, the artery was completely ligated with the other suture (twostep ligation). A dipolar electrode was stitched on the left atrialauricle for recording atrial potential. A catheter filled with a heparinsolution was inserted into the left common carotid artery for measuringthe blood pressure and for sampling the blood, and another catheter wasinserted into the left external jugular vein for administering testcompounds. All these catheters and lead wires were hypodermically guidedout of the poll. The chest was closed after administering an antibiotic(Mysyringesol for animal use), and the animal was returned to hisbreeding cage. The dog was hanged without being anesthetized on ahammock on a retention table at the time when 24 hours passed after theoperation. The test compounds were administered at a rate of 10 mg/kg/hrwhen the physical conditions of the animal has been stabilized. Theaortic blood pressure was measured using a pressure transducer. Anelectrocardiogram (standard lead II) and atrial potential were led usinga bioelectric amplifier. The heart rate was measured using the R-Rinterval on the electrocardiogram or from the blood pressure. Eachsignals were recorded with a chart recorder with verification on amonitor, while simultaneously recording on a magnetic medium using apersonal computer. An arrythmia ratio expressed by [Number ofventricular extrasystol/(Number of ventricular extrasystol+sinusrhythm)]×100 per one minute was used as an index of incidence ofarrythmia. The results are shown in Table 3. TABLE 3 Effective of theTest Compound of Example No. 146 on Arrythmia Model Induced by Two StepLigation of Canine Coronary Artery Treatment Arrythmia Ratio BeforeStart of Administration 100 15 Minutes after continued 49 Injection 30Minutes after continued 21 Injection

[0245] The results indicate that incidence of ventricular extrasystolwas suppressed by the compounds according to the present invention.

Experimental Example 4

[0246] Effect on Electrocardiogram in Rats

[0247] After anesthetizing with 1.5 g/kg (s.c.) of urethane, a rat wasfixed on a warm plate at its supination. Polyethylene tubes foradministering a test compound and for measuring the blood pressure wereinserted into and fixed to the jugular vein and femoral artery,respectively. The blood pressure of the artery was measured using apressure transducer. An electrode was attached to the animal,electrocardiograms were led by the standard lead II. The heart rate wasmeasured by using a heart rate counter. The test compound was given byintravenous injection when the blood pressure and heat rate had beenstabilized after the operation. The heart rate and blood pressure wererecorded on a chart with a recorder while simultaneously recording on amagnetic medium using a personal computer. Each parameter on theelectrocardiogram was processed using an analysis software running onthe personal computer to calculate the rate of change as compared withthat before administration. The results are shown in Table 4. TABLE 4Effect of Intravenous Administration of the Compound on PQ interval andQRS Width on the Electrocardiogram Example No. Dose (mg/kg) PQ DistanceQRS Width 146 5 — — 162 5 — — 176 5 — — 177 5 — — 196 5 — — 198 5 — —201 5 — — 226 5 — — 233 5 — — 240 5 — — 254 5 — — 278 5 — —

[0248] It was shown in this Experimental Example that the compoundsaccording to the present invention have few effects on the PQ intervaland QRS width on the electrocardiogram.

Experimental Example 5

[0249] Toxicity Test

[0250] 6-week aged female Crj(SD)IGS rats were orally given by gavagethe compounds in the Example Nos. 146, 233 and 278 once a day for 14days. No fatal cases were observed at daily dosages of 100 mg/kg or lessof the compound in the Example No. 146, of 50 mg/kg or less of thecompound in the Example No. 233 and of 20 mg/kg less of the compound inthe Example No. 278. No abnormalities were also observed in the bodyweight and general symptoms.

[0251] It was made clear that the compounds according to the presentinvention can suppress contracture of the isolated cardiac muscle cellsinduced by veratrine. The compounds according to the present inventionwere able to suppress generation of ventricular fibrillation as severearrythmia in the ischemia-reperfusion induced arrythmia model in rats,reducing mortality of the rat. Generation of ventricular extrasystol inthe arrythmia model induced by two step ligation of canine coronaryartery was also suppressed. No effects on the PQ interval and QRS widthwere observed in the compounds according to the present invention. Lowtoxicity of the compound according to the present invention wasverified, since no abnormalities were manifested in the toxicologicalstudy.

[0252] Accordingly, the compounds according to the present inventionwere shown to be effective in the arrythmia model of animals with feweffects on the electrocardiogram of the normal animals. Therefore, thecompounds are effective for the therapy and prevention of arrythmia asmedicines having no proarrythmic action.

[0253] Arrythmia is a general term of the diseases that express abnormalrhythmic function among the cardiac functions, and appears when theheart manifests abnormal excitation and conduction. While arrythmiaincludes ventricular arrythmia and atrial (supraventricular) arrythmia,the compounds according to the present invention are effective for bothtypes of symptoms. In more detail, arrythmia is classified intosupraventricular extrasystol, ventricular extrasystol, supraventriculartachycardia, WPW syndrome, atrial flutter/fibrillation, ventriculartachycardia and ventricular fibrillation.

[0254] Ventricular tachycardia and ventricular fibrillation are thoughtto be severe syndrome of arrythmia among the syndromes of ventriculararrythmia, and it is in particular suggested that these diseases may bethe causes of sudden death in the patients of ischemic heart diseasessuch as myocardial infarction and cardiac failure. Although almost allthe sudden death is caused in those suffering from some heart diseases,some of the sudden death is caused by lethal arrythmia due to overwork,although no basal diseases are observed.

[0255] The pharmaceutical composition according to the present inventionis in particular effective for therapy or prevention of ventriculartachycardia and ventricular fibrillation as severe syndromes ofarrythmia, or for prevention of sudden death.

[0256] In the pathological conditions of atrial flutter andfibrillation, it is known that atrial flutter and atrial fibrillationthemselves induce electrical remodeling to readily cause atrial flutterand atrial fibrillation again. Chemicals that suppress electricalmodeling have not been subjected to clinical medicines, and excessinflux of sodium and calcium is suggested to be the cause of thesesyndromes. Veratrine suppresses, on the other hand, inactivation of thesodium channel in the cardiac muscle cells to generate persistent sodiumcurrent, thereby induces contracture as a result of the increasedintracellular calcium concentration mediated by the sodium/calciumexchange transport system following the increased intracellular sodiumconcentration. Therefore, the compounds according to the presentinvention are thought to suppress persistent Na current. Judging fromthese results, suppression of excess influx of sodium due to thepersistent sodium current suppressing action of the compounds accordingto the present invention is effective for preventing pathologicalconditions of atrial flutter and fibrillation from developing.

[0257] The compound according to the present invention has the activityfor suppressing contracture of the isolated cardiac muscle cells inducedby veratrine while suppressing persistent sodium current. Therefore, thecompounds according to the present invention may be also used fortherapy or amelioration of disorders such as cardiac failure, anginapectoris, myocardial infarction, injury of cardiovascular systemaccompanied with revascularization by PTCA/PTCR/CAGB, injury of thecardiac muscle caused by ischemia-reperfusion (except severe arrythmia),acute phase in cerebral infarction, cerebral hemorrhage, transientcerebral ischemia, subarachnoid hemorrhage, head trauma, sequela ofsurgical operation of the brain, cerebrovascular disease such as sequelaof cerebral arteriosclerosis, failure of implanted organs afterimplantation, symptoms caused by temporary hemostasis at surgicaloperation of the organs, convulsions, epilepsy, dementia(cerebrovascular and senile), neuralgia, migraine, neuropathic pain,digitalis intoxication, monkshood poisoning and pyrethroid insecticidepoisoning. The compounds according to the present invention may be alsoused for hyperkalemic periodic paralysis, myotonia congenita, and longQT syndrome that are congenital diseases and caused by abnormalinactivation of the sodium channel due to abnormal sodium channel genes,i.e., by generation of persistent sodium current.

[0258] The drug according to the present invention is administered asformulations of the pharmaceutical compositions.

[0259] The pharmaceutical compositions according to the presentinvention may comprise at least one of the compound represented by theformula (I) according to the present invention, and it may be combinedwith pharmaceutically acceptable additives. In more detail, the compoundaccording to the present invention may be appropriately combined withthe following additives to form various formulations: excipients (forexample lactose, sucrose, mannitol, crystalline cellulose and silicicacid), binders (for example, crystalline cellulose, sugars (mannitol,sucrose, sorbitol, erythritol and xylitol), dextrine, hydroxypropylcellulose (HPC), hydroxypropylmethyl cellulose (HPMC),polyvinylpyrrolidone (PVP) and macrogol), lubricants (for example,magnesium stearate, calcium stearate and talc), colorants, flavoringagents, disintegrants (for example corn starch and carboxymethylcellulose), antiseptics (benzalkonium chloride and paraoxybenzoic acidester), isotonic agents (for example, glycerine, sodium chloride,calcium chloride, mannitol and glucose), pH adjustment agents (sodiumhydroxide, potassium hydroxide, sodium carbonate, hydrochloric acid,sulfuric acid and a buffer solution such as phosphate buffer),stabilizers (for example sugar, sugar alcohol and xanthan gum),dispersion agents, antioxidants (for example, ascorbic acid,butylhydroxyanisole (BHA), propyl gallate and d1-α-topcopherol),buffers, preservatives (for example, paraben, benzyl alcohol andbenzalkonium chloride), aromatics (for example, vanilin, 1-menthol androse oil), dissolution aids (for example, polyoxyethylene hardenedcastor oil, Polysorbate 80, polyethylene glycol, phospholipidcholesterol and triethanolamine), absorption accelerators (for example,sodium glycolate, disodium edatate, sodium caprate, acyl carnitine andlimone), gelation agents, suspending agents, surface active agents oremulsifying agents, and suitable additives and solvents which arenormally used.

[0260] Such formulations include tablets, capsules, granules, powers,suppository, pessary, sublingual tablets, buccal tablets, oral cavitydisintegrants, mastication tablets, troches, jelly compositions, pastecompositions, patch agents for tunica mucous oris, syrup (oral liquidand emulsion), inhalants, injection formulation, a nasal formulation(liquid and powder), external agents (ointment, cream, jelly, gelatiumagent), stick agents (tape, patch, cataplasm), liquid formulation,suspending agents and spray formulation. These formulations may beadministered to a patient orally or parenterally (for example,intravenous injection, intra-arterial injection, hypodermicadministration, intramuscular injection, intrarectal administration,vaginal administration, intranasal administration, or absorption via themucous membrane such as oral cavity mucous membrane and penial mucousmembrane).

[0261] While the dosage of the compounds according to the presentinvention is usually 0.1 mg to 2.5 g a day for an adult, preferably 0.5mg to 1.0 g, and more preferably 1 mg to 500 mg, it may be appropriatelyincreased or decreased depending on disease conditions andadministration route.

[0262] The entire quantity may be orally or parenterally given by two tosix times administration, or may be continuously injected by intravenousdrip.

EXAMPLES

[0263] While the following examples are provided for describing thepresent invention in more detail, the present invention is notrestricted thereto. Nuclear magnetic resonance (NMR) spectra weremeasured by using JEOL JNM-EX270 FT-NMR (manufactured by JEOL Ltd.; dataobtained by this instrument are marked by *) or JEOL JNM-LA300 FT-NMR(manufactured by JEOL Ltd.). Infra-red (IR) spectra were measured byusing HORIBA FT-200 or FT-720 (manufactured by Horiba Seisakusho Co.).Melting points were measured by using Mettler FP80 or FP90(mannufactured by Mettler Co.).

Example 1

[0264] Synthesis of1-Benzyl-4-[2-[N-(4-methoxyphenyl)-N-methylamino]ethyl]piperidin-4-ol

[0265] Step 1

[0266] Synthesis ofN-(4-methoxyphenyl)-N-methyl-2-(1-benzyl-4-hydroxypiperidin-4-yl)acetamide

[0267] A solution of 4′-methoxy-N-methylacetanilide (12 g) in ananhydrous tetrahydrofuran (30 mL) was added to a solution in ananhydrous tetrahydrofuran (100 mL) of lithium diisopropylamide preparedfrom diisopropylamine (10.5 mL) and n-butyl lithium (1.53M hexanesolution; 48 mL) at below −65° C., and the mixture was stirred at −78°C. for 15 minutes. An anhydrous tetrahydrofuran solution (20 mL) of1-benzylpiperidin-4-one (12.7 g) was then added to this reaction mixtureat below −65° C., and the resulting mixture was stirred at −78° C. for10 minutes. After increasing the temperature to room temperature, waterwas added to the mixture, and the mixed solution was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine and dried over anhydrous sodium sulfate, followed by distillingoff the solvent under reduced pressure. The residue obtained wasrecrystallized from ether-hexane to obtain the titled compound (17.2 g).

[0268] Step 2

[0269] Synthesis of1-benzyl-4-[2-[N-(4-methoxyphenyl)-N-methylamino]ethyl]piperidin-4-ol

[0270] A solution of borane-methyl sulfide complex (10M, 13.5 mL) wasadded to a solution in an anhydrous tetrahydrofuran (150 mL) of thecompound (10 g) obtained in the Step 1, and the mixed solution washeated under reflux for 2 hours. After allowing the solution to cool,methanol (10 mL) and 10% hydrogen chloride in methanol (10 mL) was addedto the solution, followed by heating under reflux for 2 hours. Aftercooling, the solvent was distilled off under reduced pressure. Thesolution was added with water and saturated aqueous sodium bicarbonateto make an alkaline solution and extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine. After dryingthe organic layer over anhydrous sodium sulfate, the solvent wasdistilled off under reduced pressure. The residue obtained was purifiedthrough silica gel column chromatography (elution solvent:methylenechloride:methanol=49:1 to 9:1) to obtain the titled compound (8.2 g).

Example 2

[0271] Synthesis of1-benzyl-4-[2-[N-(4-ethoxyphenyl)-N-methylamino]ethyl]piperidin-4-ol

[0272] Step 1

[0273] Synthesis ofN-(4-ethoxyphenyl)-N-methyl-2-(1-benzyl-4-hydroxypiperidin-4-yl)acetamide

[0274] A solution of 4′-ethoxy-N-methylacetanilide (0.97 g) in ananhydrous tetrahydrofuran (30 mL) was cooled to −78° C. under an argonatmosphere, and lithium hexamethyldisilazide (1M tetrahydrofuransolution; 6 mL) was added to the solution at below −65° C., followed bystirring at −78° C. for 15 minutes. Subsequently,1-benzylpiperidin-4-one (1.1 g) was added to the reaction mixture atbelow −65° C., and the mixed solution was stirred at −78° C. for 10minutes. After increasing the temperature to room temperature, water wasadded to the mixture and extracted with ethyl acetate. The organic layerwas washed with water and saturated brine and dried over anhydroussodium sulfate, and the solvent was distilled off under reducedpressure. The titled compound (1.08 g) was obtained by recrystallizationof the obtained residue from hexane.

[0275] Step 2

[0276] Synthesis of1-benzyl-4-[2-[N-(4-ethoxyphenyl)-N-methylamino]ethyl]piperidin-4-ol

[0277] The titled compound (0.79 g) was obtained by the same method asin the Step 2 in the Example 1 by using the compound (1.0 g) obtained inthe Step 1.

Example 3

[0278] Synthesis of1-benzyl-4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]piperidin-4-ol

[0279] Step 1

[0280] Synthesis ofN-(4-n-butoxyphenyl)-N-methyl-2-(1-benzyl-4-hydroxypiperidin-4-yl)acetamide

[0281] A solution of 4′-n-butoxy-N-methylacetanilide (0.34 g) inanhydrous tetrahydrofuran (1.5 mL) was added to a solution of lithiumdiisopropylamide prepared from diisopropylamine (0.22 mL) and n-butyllithium (1.58M hexane solution; 1.07 mL) in an anhydrous tetrahydrofuran(1.6 mL) under cooling with ice-water, and the mixture was stirred for30 minutes. A solution of 1-benzylpiperidin-4-one (0.32 g) in anhydroustetrahydrofuran solution (1.5 mL) was added to thereto under coolingwith ice-water, followed by additional stirring for 30 minutes. Afterincreasing the temperature to room temperature, water was added to themixture and extracted with ethyl acetate. The organic layer was washedwith water and saturated brine and dried over anhydrous sodium sulfate.The solvent was distilled off. The titled compound (0.33 g) was obtainedby recrystallization of the residue from hexane.

[0282] Step 2

[0283] Synthesis of1-benzyl-4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]piperidin-4-ol

[0284] The titled compound (0.28 g) was obtained by the same method asin the Step 2 in the Example 1 using the compound (0.3 g) obtained inthe Step 1.

[0285] The following compounds were synthesized by any one of the methodin the Step 1 in the Examples 1 to 3, and by the same method as in theStep 2 in the Example 1.

Example 4

[0286]1-Benzyl-4-[2-[N-methyl-N-(4-isopropoxyphenyl)-amino]ethyl]piperidin-4-ol

[0287] Step 1

[0288]N-methyl-N-(4-isopropoxyphenyl)-2-(1-benzyl-4-hydroxypiperidin-4-yl)acetamide

[0289] Step 2

[0290]1-benzyl-4-[2-[N-methyl-N-(4-isopropoxyphenyl)-amino]ethyl]piperidin-4-ol

Example 5

[0291]1-Benzyl-4-[2-[N-(4-cyclohexyloxyphenyl)-N-methylamino]-ethyl]piperidin-4-ol

[0292] Step 1

[0293]N-(4-cyclohexyloxyphenyl)-N-methyl-2-(1-benzyl-4-hydroxypiperidin-4-yl)acetamide

[0294] Step 2

[0295]1-benzyl-4-[2-[N-(4-cyclohexyloxyphenyl)-N-methylamino]ethyl]piperidin-4-ol

Example 6

[0296] 1-Benzyl-4-[2-[N-methyl-N-(4-phenoxyphenyl)amino]ethyl]-piperidin-4-ol

[0297] Step 1

[0298]N-methyl-N-(4-phenoxyphenyl)-2-(1-benzyl-4-hydroxypiperidin-4-yl)acetamide

[0299] Step 2

[0300]1-Benzyl-4-[2-[N-methyl-N-(4-phenoxyphenyl)-amino]ethyl]piperidin-4-ol

Example 7

[0301]1-Benzyl-4-[2-[N-(3-n-butoxyphenyl)-N-methylamino]-ethyl]piperidin-4-ol

[0302] Step 1

[0303]N-(3-n-butoxyphenyl)-N-methyl-2-(1-benzyl-4-hydroxypiperdin-4-yl)acetamide

[0304] Step 2

[0305]1-Benzyl-4-[2-[N-(3-n-butoxyphenyl)-N-methylamino]ethyl]piperidin-4-ol

Example 8

[0306]1-Benzyl-4-[2-[N-(2-n-butoxyphenyl)-N-methylamino]-ethyl]piperidin-4-ol

[0307] Step 1

[0308]N-(2-n-butoxyphenyl)-N-methyl-2-(1-benzyl-4-hydroxypiperidin-4-yl)acetamide

[0309] Step 2

[0310]1-Benzyl-4-[2-[N-(2-n-butoxyphenyl)-N-methylamino]ethyl]piperidin-4-ol

Example 9

[0311]1-Benzyl-4-[2-[N-(4-n-butoxy-3-fluorophenyl)-N-methylamino]ethyl]piperidin-4-ol

[0312] Step 1

[0313]N-(4-n-butoxy-3-fluorophenyl)-N-methy-2-(1-benzyl-4-hydroxypiperidin-4-yl)acetamide

[0314] Step 2

[0315]1-Benzyl-4-[2-[N-(4-n-butoxy-3-fluorophenyl)-N-methylamino]ethyl]piperidin-4-ol

Example 10

[0316]1-Benzyl-4-[2-[N-methyl-N-(4-n-propylphenyl)amino]-ethyl]piperidin-4-ol

[0317] Step 1

[0318]N-methyl-N-(4-n-propylphenyl)-2-(1-benzyl-4-hydroxypiperidin-4-yl)acetamide

[0319] Step 2

[0320]1-Benzyl-4-[2-[N-methyl-N-(4-n-propylphenyl)-amino]ethyl]piperidin-4-ol

Example 11

[0321]1-Benzyl-4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]-1-methoxyethyl]piperidin-4-ol

[0322] Step 1

[0323]N-(4-n-butoxyphenyl)-N-methy-2-(1-benzyl-4-hyrdoxypiperidin-4-yl)-2-methoxyacetamide

[0324] Step 2

[0325]1-Benzyl-4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]-1-methoxyethyl]piperidin-4-ol

Example 12

[0326] Synthesis of1-benzyl-4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]-1-hydroxyethyl]piperidin-4-ol

[0327] Step 1

[0328] Synthesis ofN-(4-n-butoxyphenyl)-N-methyl-2-tert-butyldimethylsilyloxy-2-(1-benzyl-4-hydroxypiperidin-4-yl)acetamide

[0329] The titled compound (0.75 g) was obtained by the same method asin the Step 1 in the Example 1 by using4′-n-butoxy-2-tert-butyldimethylsilyloxy-N-methylacetanilide (3.85 g).

[0330] Step 2

[0331] Synthesis of1-benzyl-4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]-1-hydroxyethyl]piperidin-4-ol

[0332] The titled compound (0.48 g) was obtained by the same method asin the Step 2 in the Example 1 by using the compound (0.70 g) obtainedin the Step 1, wherein the silyl group was simultaneously removed bytreating with hydrochloric acid.

Example 13

[0333] Synthesis of1-benzyl-4-[2-[N-(4-n-butoxyphenyl)-amino]ethyl]piperidin-4-ol

[0334] Step 1

[0335] Synthesis ofN-(4-n-butoxyphenyl)-2-(1-benzyl-4-hydroxypiperidin-4-yl)acetamide

[0336] To a solution of (1-benzyl-4-hydroxypiperidin-4-yl) acetic acidlithium salt (3.09 g) in methylene chloride (60 mL) were added4-n-butoxyaniline (2.0 g) and pyridine (2.14 mL). Phosphorousoxychloride (1.19 mL) was added dropwise to the solution under coolingwith an ice-sodium chloride, followed by stirring at 5 to 10° C. for 1hour. The mixture was made alkaline with saturated aqueous sodiumbicarbonate under cooling with an ice-water, and the solution wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine and dried over anhydrous sodium sulfate, and then,the solvent was distilled off under reduced pressure. The residue waspurified with silica gel column chromatography (elution solvent;methylene chloride:methanol=19:1 to 9:1) to obtain the titled compound(1.15 g).

[0337] Step 2

[0338] Synthesis of1-benzyl-4-[2-[N-(4-n-butoxyphenyl)amino]ethyl]piperidin-4-ol The titledcompound (0.42 g) was obtained by the same method as in the Step 2 inthe Example 1 by using the compound (0.5 g) obtained in the step 1.

Example 14

[0339] Synthesis of1-benzyl-4-[2-[N-methyl-N-(4-n-propoxyphenyl)amino]ethyl]piperidin-4-ol

[0340] Step 1

[0341] Synthesis of1-benzyl-4-[2-[N-(4-hydroxyphenyl)-N-methylamino]ethyl]piperidin-4-ol

[0342] To an acetic acid solution (51 mL) of the compound (7.12 g)obtained in the Step 2 in the Example 1, 48% hydrobromic acid (51 mL)was added, and the solution was heated under reflux for 5 hours. Afterconcentrating the reaction solution under reduced pressure, the residuewas dissolved in water. The aqueous solution was made alkaline withsaturated aqueous sodium bicarbonate, and was extracted with ethylacetate. The organic layer was washed with water and saturated brine,dried over anhydrous sodium sulfate, and the solvent was distilled offunder reduced pressure. The residue obtained was purified by silica gelcolumn chromatography [Chromatorex NH™] (elution solvent; ethylacetate:hexane=1:1 to ethyl acetate:methanol=19:1) to obtain the titledcompound (3.91 g).

[0343] Step 2

[0344] Synthesis of1-benzyl-4-[2-[N-methyl-N-(4-n-propoxyphenyl)amino]ethyl]piperidin-4-ol

[0345] To an anhydrous dimethylformamide solution (8 mL) of the compound(500 mg) obtained in the Step 1 was added sodium hydride (60% dispersionin oil; 70 mg) under ice-cooling, and stirred for 30 minutes. Then,n-propyl bromide (217 mg) was added and the solutionn was stirred at 10°C. for 5 hours. The mixture was poured into water, and the aqueousmixture was extracted with ethyl acetate. The organic layer was washedwith water and saturated brine, dried over anhydrous sodium sulfate, thesolvent was distilled off under reduced pressure. The residue obtainedwas purified by silica gel column chromatography [Chromatorex NH™] (elution solvent; ethyl acetate:hexane=1:3) to obtain the titled compound(82 mg).

[0346] The following compounds were obtained by the same method as inthe Step 2 in the Example 14.

Example 15

[0347]1-Benzyl-4-[2-[N-methyl-N-(4-n-pentyloxyphenyl)-amino]ethyl]piperidin-4-ol

Example 16

[0348]1-Benzyl-4-[2-[N-(4-isobutoxyphenyl)-N-methylamino]-ethyl]piperidin-4-ol

Example 17

[0349]1-Benzyl-4-[2-[N-(4-cyclobutoxyphenyl)-N-methylamino]-ethyl]piperidin-4-ol

Example 18

[0350]1-Benzyl-4-[2-[N-methyl-N-(4-cyclopropylmethyloxyphenyl)-amino]ethyl]piperidin-4-ol

Example 19

[0351] Synthesis of4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(3,4-methylenedioxyphenylmethyl)-piperidin-4-ol

[0352] Step 1

[0353] Synthesis of4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]piperidin-4-ol

[0354] Ammonium formate (0.48 g) and 10% palladium on carbon (0.1 g)were added to a methanol solution (10 mL) of the compound (1.0 g)obtained in the Step 2 in the Example 3, and the mixture was heatedunder reflux for 1 hour. After cooling, the catalyst was filtered off,and the filtrate was concentrated under reduced pressure. A saturatedaqueous sodium bicarbonate was added to the residue to make the solutionalkaline, and the aqueous solution was extracted with methylenechloride. The organic layer was washed with water and saturated brine,and dried over anhydrous sodium sulfate. The titled compound (0.75 g)was obtained by distilling off the solvent.

[0355] Step 2

[0356] Synthesis of4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(3,4-methylenedioxyphenyl-methyl)-piperidin-4-ol

[0357] Piperonal (0.21 g) and acetic acid (0.14 mL), and then sodiumtriacetoxyborohydride (0.58 g) were added to an anhydrous methylenechloride solution (10 mL) of the compound (0.42 g) obtained in the Step1, and the mixed solution was stirred overnight under an argonatmosphere. The reaction solution was made alkaline by adding saturatedaqueous sodium bicarbonate solution, and was extracted with methylenechloride. The organic layer was washed with water and saturated brine,and dried over anhydrous sodium sulfate. The solvent was distilled offunder reduced pressure. The residue was purified by silica gel columnchromatography (elution solvent; methylene chloride:methanol=49:1 to19:1) to obtain the titled compound (0.46 g)

[0358] The following compounds were synthesized by the same method as inthe Step 2 in the Example 19.

Example 20

[0359]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(4-chlorophenylmethyl)piperidin-4-ol

Example 21

[0360]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-[4-(trifluoromethyl)phenylmethyl]piperidin-4-ol

Example 22

[0361]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1(4-cyanophenylmethyl)piperidin-4-ol

Example 23

[0362]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(4-methoxycarbonylphenylmethyl)piperidin-4-ol

Example 24

[0363]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-[4-(dimethylamino)phenylmethyl]piperidin-4-ol

Example 25

[0364]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(4-hydroxyphenylmethyl)piperidin-4-ol

Example 26

[0365]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(4-methoxyphenylmethyl)piperidin-4-ol

Example 27

[0366]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(3-methoxyphenylmethyl)piperidin-4-ol

Example 28

[0367]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(2-methoxyphenylmethyl)piperidin-4-ol

Example 29

[0368]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(3-fluorophenylmethyl)piperidin-4-ol

Example 30

[0369]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(3,4-difluorophenylmethyl)piperidin-4-ol

Example 31

[0370]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]l-1(4-methylphenylmethyl)piperidin-4-ol

Example 32

[0371]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(2,3-dihydro-1H-indene-2-yl)piperidin-4-ol

Example 33

[0372] Synthesis of4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-[2-(4-fluorophenyl)ethyl]piperidin-4-ol

[0373] Step 1

[0374] Synthesis of4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-[(4-fluorophenyl)acetyl]-piperidin-4-ol

[0375] To an anhydrous methylene chloride solution (5 mL) of thecompound (0.52 g) obtained in the Step 1 in the Example 19 and4-fluorophenylacetic acid (0.29 g) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.36 g),and the mixture was stirred at room temperature for 1 hour. Water wasadded to the solution and then, the mixed solution was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, and the organic layer was dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure. The residueobtained was purified by silica gel column chromatography (elutionsolvent; methylene chloride:methanol=97:3 to 19:1) to obtain the titledcompound (0.72 g).

[0376] Step 2

[0377]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-[2-(4-fluorophenyl)ethyl]piperidin-4-ol

[0378] The titled compound (0.59 g) was obtained by the same method asin the Step 2 in the Example 1 by using the compound (0.71 g) obtainedin the Step 1.

Example 34

[0379] Synthesis of4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(4-fluorophenylmethyl)piperidin-4-ol

[0380] To an anhydrous methylene chloride solution (5 mL) of thecompound (0.30 g) obtained in the Step 1 in the Example 19 were added4-fluorobenzylbromide (0.13 mL) and triethylamine (0.14 mL) undercooling with ice-water. The mixed solution was stirred under coolingwith ice-water for 2 hours, and at room temperature for 2 hours. Thereaction solution was poured into ice water, and the mixed solution wasmade alkaline by adding saturated aqueous sodium bicarbonate, followedby extraction with ethyl acetate. The organic layer was washed withwater and saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure. The residue obtainedwas purified by silica gel column chromatography (elution solvent;methylene chloride:methanol=97:3 to 19:1) to obtain the titled compound(0.28 g).

[0381] The following compounds were synthesized by the same method as inthe Example 34.

Example 35

[0382]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1(1-phenylethyl)piperidin-4-ol

Example 36

[0383]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-benzoylmethylpiperidin-4-ol

Example 37

[0384]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(4-fluorobenzoylmethyl)piperidin-4-ol

Example 38

[0385] Synthesis of4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]-1-methoxyethyl]-1-(2-phenylethyl)piperidin-4-ol

[0386] Step 1

[0387] Synthesis of4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]-1-methoxyethyl]piperidin-4-ol

[0388] To a methanol solution (50 mL) of the compound (0.62 g) obtainedin the Step 2 in the Example 11 was added 10% palladium on carbon (0.1g), and the mixture was stirred at room temperature for 2 days under ahydrogen atmosphere. The catalyst was filtered off, and the filtrate wasconcentrated under reduced pressure to obtain the titled compound (0.42g).

[0389] Step 2

[0390] Synthesis of4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]-1-methoxyethyl]-1-(2-phenylethyl)-piperidin-4-ol

[0391] The titled compound (0.45 g) was obtained by the same method asin the Example 34 by using the compound (0.39 g) obtained in the step 1and phenethyl bromide (0.26 g).

Example 39

[0392] Synthesis of4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]-ethyl]-1-[2-(4-methoxyphenyl)ethyl]piperidin-4-ol

[0393] Step 1

[0394] Synthesis ofN-(4-n-butoxyphenyl)-N-methy-2-(4-hydroxypiperidin-4-yl)acetamide

[0395] The crude product obtained by the same method as in the Step 1 inthe Example 19 by using the compound (0.62 g) obtained in the step 1 inthe Example 3 was purified by silica gel column chromatography[Chromatorex NH™] (elution solvent; methylene chloride:methanol=19:1) toobtain the titled compound (0.48 g).

[0396] Step 2

[0397] Synthesis ofN-(4-n-butoxyphenyl)-N-methyl-2-[4-hydroxy-1-[(4-methoxyphenyl)acetyl]piperidin-4-yl]acetamide

[0398] The titled compound (0.95 g) was obtained by the same method asin the Step 1 in the Example 33 by using the compound (0.71 g) obtainedin the Step 1.

[0399] Step 3

[0400] Synthesis of4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]-ethyl]-1-[2-(4-methoxyphenyl)ethyl]piperidin-4-ol

[0401] The titled compound (0.58 g) was obtained by the same method asin the Step 2 in the Example 1 by using the compound (0.95 g) obtainedin the Step 2.

[0402] The following compounds were synthesized by the same methods asin the Steps 2 and 3 in the Example 39.

Example 40

[0403]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-[2-(2,4-difluorophenyl)ethyl]piperidin-4-ol

[0404] Step 1

[0405]N-(4-n-butoxyphenyl)-N-methyl-2-[1-(2,4-difluorophenyl)acetyl-4-hydroxypiperidin-4-yl]acetamide

[0406] Step 2

[0407]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-[2-(2,4-difluorophenyl)ethyl]piperidin-4-ol

Example 41

[0408]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-[2-(3,4-methylenedioxyphenyl)ethyl]piperidin-4-ol

[0409] Step 1

[0410]N-(4-n-butoxyphenyl)-N-methyl-2-[4-hydroxy-1-[(3,4-methylenedioxyphenyl)acetyl]piperidin-4-yl]acetamide

[0411] Step 2

[0412]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-[2-(3,4-methylenedioxyphenyl)ethyl]piperidin-4-ol

Example 42

[0413]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]l-1(3-phenylpropyl)piperidin-4-ol

[0414] Step 1

[0415]N-(4-n-butoxyphenyl)-N-methyl-2-[4-hydroxy-1-(3-phenylpropionyl)piperidin-4-yl]acetamide

[0416] Step 2

[0417]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(3-phenylpropyl)piperidin-4-ol

Example 43

[0418]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(2-phenoxyethyl)piperidin-4-ol

[0419] Step 1

[0420]N-(4-n-butoxyphenyl)-N-methyl-2-[4-hydroxy-1-(phenoxyacetyl)piperidin-4-yl]acetamide

[0421] Step 2

[0422]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(2-phenoxyethyl)piperidin-4-ol

Example 44

[0423] Synthesis of4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]-ethyl]-1-(2-phenylethyl)piperidin-4-ol

[0424] Step 1

[0425] Synthesis ofN-(4-n-butoxyphenyl)-N-methyl-2-[4-hydroxy-1-(phenylacetyl)piperidin-4-yl]acetamide

[0426] Triethylamine (0.37 mL) and then phenylacetyl chloride (0.32 mL)were added to an anhydrous methylene chloride solution (9 mL) of thecompound (0.71 g) obtained in the Step 1 in the Example 39, and themixed solution was stirred at room temperature for 5 hours. The reactionsolution was poured into ice-water, and saturated aqueous sodiumbicarbonate solution was added to make the solution alkaline, followedby extraction with methylene chloride. The organic layer was washed withwater and saturated brine, dried over anhydrous sodium sulfate, and thesolvent was distilled off under a reduced pressure. The residue obtainedwas purified by silica gel column chromatography (elution solvent; ethylacetate:hexane=3:7 to ethyl acetate) to obtain the titled compound (0.62g).

[0427] Step 2

[0428] Synthesis of4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(2-phenylethyl)piperidin-4-ol

[0429] The titled compound (0.38 g) was obtained by the same method asin the step 2 in the Example 1 by using the compound (0.62 g) obtainedin the Step 1.

Example 45

[0430] Synthesis of4-[2-[N-(4-n-butoxyphenyl)amino]ethyl]-1-[2-(4-fluorophenyl)ethyl]piperidin-4-ol

[0431] Step 1

[0432] Synthesis ofN-(4-n-butoxyphenyl)amino-2-(4-hydroxypiperidin-4-yl)acetamide

[0433] The titled compound (3.0 g) was obtained by the same method as inthe Step 1 in the Example 38 by using the compound (4.0 g) obtained inthe Step 1 in the Example 13.

[0434] Step 2

[0435] Synthesis ofN-(4-n-butoxyphenyl)-2-[4-hydroxy-1-[(4-fluorophenyl)acetyl]piperidin-4-yl]acetamide

[0436] The titled compound (0.62 g) was obtained by the same method asin the Step 1 in the Example 33 by using the compound (0.50 g) obtainedin the Step 1.

[0437] Step 3

[0438] Synthesis of4-[2-[N-(4-n-butoxyphenyl)amino]ethyl]-1-[2-(4-fluorophenyl)ethyl]piperidin-4-ol

[0439] The titled compound (0.49 g) was obtained by the same method asin the Step 2 in the Example 1 by using the compound (0.60 g) obtainedin the Step 2.

Example 46

[0440] Synthesis of4-[2-[N-(4-cyclobutoxyphenyl)-N-methylamino]ethyl]-1-(2-phenylethyl)piperidin-4-ol

[0441] Step 1

[0442] Synthesis ofN-(4-cyclobutoxyphenyl)-N-methyl-2-(1-benzyl-4-hydroxypiperidin-4-yl)acetamide

[0443] The titled compound (1.60 g) was obtained by the same method asin the Step 1 in the Example 13 by using 4-cyclobutoxy-N-methylaniline(1.2 g).

[0444] Step 2

[0445] Synthesis ofN-(4-cyclobutoxyphenyl)-N-methyl-2-(4-hydroxypiperidin-4-yl)acetamide

[0446] The titled compound (1.25 g) was obtained by the same method asin the Step 1 in the Example 38 by using the compound (1.60 g) obtainedin the Step 1.

[0447] Step 3

[0448] Synthesis ofN-(4-cyclobutoxyphenyl)-N-methyl-2-[4-hydroxy-1-(phenylacetyl)piperidin-4-yl]acetamide

[0449] The titled compound (0.43 g) was obtained by the same method asin the Step 1 in the Example 44 by using the compound (0.35 g) obtainedin the Step 2.

[0450] Step 4

[0451] Synthesis of4-[2-[N-(4-cyclobutoxyphenyl)-N-methylamino]ethyl]-1-(2-phenylethyl)piperidin-4-ol

[0452] The titled compound (0.35 g) was obtained by the same method asin the Step 2 in the Example 1 by using the compound (0.40 g) obtainedin the Step 3.

Example 47

[0453] Synthesis of4-[2-[N-(4-cyclobutoxyphenyl)-N-methylamino]ethyl]-1-[2-(4-fluorophenyl)ethyl]piperidin-4-ol

[0454] Step 1

[0455]N-(4-cyclobutoxyphenyl)-N-methyl-2-[1-[(4-fluorophenyl)acetyl]-4-hydroxypiperidin-4-yl]acetamide

[0456] The titled compound (0.92 g) was obtained by the same method asin the Step 1 in the Example 33 by using the compound (0.82 g) obtainedin the Step 2 in the Example 46.

[0457] Step 2

[0458]4-[2-[N-(4-cyclobutoxyphenyl)-N-methylamino]ethyl]-1-[2-(4-fluorophenyl)ethyl]piperidin-4-ol

[0459] The titled compound (0.63 g) was obtained by the same method asin the Step 2 in the Example 1 by using the compound (0.91 g) obtainedin the Step 1

[0460] The following compounds were obtained by the same methods as inthe Steps 1 and 2 in the example 47.

Example 48

[0461]4-[2-[N-(4-cyclobutoxyphenyl)-N-methylamino]ethyl]-1-[2-(2-chlorophenyl)ethyl]piperidin-4-ol

[0462] Step 1

[0463]N-(4-cyclobutoxyphenyl)-N-methy-2-[1-(2-chlorophenyl)acetyl-4-hydroxypiperidin-4-yl]acetamide

[0464] Step 2

[0465]4-[2-[N-(4-cyclobutoxyphenyl)-N-methylamino]ethyl]-1-[2-(2-chlorophenyl)ethyl]piperidin-4-ol

Example 49

[0466] Synthesis of4-[2-[N-[4-n-butoxy-3-(hydroxymethyl)phenyl]-N-methylamino]ethyl]-1-[2-(4-fluorophenyl)ethyl]piperidin-4-ol

[0467] Step 1

[0468] Synthesis ofN-(4-n-butoxy-3-methoxycarbonylphenyl)-N-methyl-2-(1-benzyl-4-hydroxypiperidin-4-yl)acetamide

[0469] The titled compound (1.18 g) was obtained by the same method asin the Step 1 in the Example 13 by using lithium(1-benzyl-4-hydroxypiperidin-4-yl)acetate (2.159 g) and methyl2-n-butoxy-5-(methylamino)benzoate (2.00 g).

[0470] Step 2

[0471] Synthesis ofN-(4-n-butoxy-3-methoxycarbonylphenyl)-N-methyl-2-(4-hydroxypiperidin-4-yl)acetamide

[0472] The titled compound (0.88 g) was obtained by the same method asin the Step 1 in the Example 19 by using the compound (1.18 g) obtainedin the Step 1.

[0473] Step 3

[0474] Synthesis ofN-(4-n-butoxy-3-methoxycarbonylphenyl)-N-methyl-2-[1-(4-fluorophenyl)acetyl-4-hydroxypiperidin-4-yl]acetamide

[0475] The titled compound (1.23 g) was obtained by the same method asin the Step 1 in the Example 33 by using the compound (0.88 g) obtainedin the Step 2 and 4-fluorophenyl acetic acid (0.43 g).

[0476] Step 4

[0477] Synthesis ofN-(4-n-butoxy-3-carboxyphenyl)-N-methyl-2-[1-(4-fluorophenyl)acetyl-4-hydroxypiperidin-4-yl]acetamide

[0478] An aqueous solution (2.7 mL) of lithium hydroxide monohydrate(0.20 g) was added to a methanol solution (7 mL) of the compound (1.23g) obtained in the Step 3, and the mixture was refluxed for 10 minuteswith heating. The solvent was distilled off under reduced pressure aftercooling. Water was added to the residue, and the solution was washedwith ethyl acetate. The aqueous layer was adjusted to pH 3 with 1Nhydrochloric acid, and extracted with methylene chloride. The organiclayer was washed with water and saturated brine and dried over anhydroussodium sulfate. The titled compound (1.19 g) was obtained by distillingoff the solvent.

[0479] Step 5

[0480] Synthesis of4-[2-[N-[4-n-butoxy-3-(hydroxymethyl)phenyl]-N-methylamino]ethyl]-1-[2-(4-fluorophenyl)ethyl]piperidin-4-ol

[0481] The titled compound (0.78 g) was obtained by the same method asin the Step 2 in the Example 1 by using the compound (1.19 g) obtainedin the Step 4.

Example 50

[0482] Synthesis of4-[2-[N-[4-n-butoxy-2-(hydroxymethyl)phenyl]-N-methylamino]ethyl]-1-[2-(3,4-methylenedioxy-phenyl)ethyl]piperidin-4-ol

[0483] Step 1

[0484] Synthesis of tert-butyl[4-hydroxy-1-[(3,4-methylenedioxyphenyl)acetyl]piperidin-4-yl]acetate

[0485] The titled compound (3.25 g) was obtained by the same method asin the Step 1 in the Example 33 by using tert-butyl(4-hydroxypiperidin-4-yl)acetate (2.0 g) which is obtained fromtert-butyl (4-hydroxy-1-benzylpiperidin-4-yl)acetate by the same methodas in the Step 1 in the Example 38 and 3,4-methylenedioxyphenylaceticacid (2.0 g).

[0486] Step 2

[0487] Synthesis of[4-hydroxy-1-[(3,4-methylenedioxyphenyl)-acetyl]piperidin-4-yl]aceticacid

[0488] Anisole (1.5 mL) and the compound (1.6 g) obtained in the Step 1were added to ice-cooled trifluoroacetic acid (5 mL). The mixture wasstirred at room temperature for 2 hours. The reaction solution wasconcentrated under reduced pressure, ether was added to the residue, andthe mixture was extracted with 1N aqueous sodium hydroxide solution. Theaqueous layer was adjusted to pH 2 by adding conc. hydrochloric acid,and was extracted with methylene chloride. The organic layer was washedwith saturated brine and dried over anhydrous sodium sulfate. Thesolvent was distilled off under a reduced pressure. The residue obtainedwas recrystallized from ether to obtain the titled compound (1.25 g).

[0489] Step 3

[0490] Synthesis ofN-[4-n-butoxy-2-(hydroxymethyl)phenyl]-N-methyl-2-[4-hydroxy-1-[(3,4-methylenedioxyphenyl)-acetyl]piperidin-4-yl]acetamide

[0491] The titled compound (1.60 g) was obtained by the same method asin the Step 1 in the Example 33 by using the compound (1.2 g) obtainedin the Step 2 and 4-n-butoxy-2-(hydroxymethyl)-N-methylaniline (0.94 g).

[0492] Step 4

[0493] Synthesis of4-[2-[N-[4-n-butoxy-2-(hydroxymethyl)-phenyl]-N-methylamino]ethyl]-1-[2-(3,4-methylenedioxyphenyl)ethyl]piperidin-4-ol

[0494] The titled compound (1.02 g) was obtained by the same method asin the Step 2 in the Example 1 by using the compound (1.50 g) obtainedin the Step 3.

Example 51

[0495] Synthesis of4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]-1-hydroxyethyl]-1-(2-phenylethyl)piperidin-4-ol

[0496] Step 1

[0497] Synthesis ofN-(4-n-butoxyphenyl)-N-methy-2-(1-benzyl-4-hydroxypiperidin-4-yl)-2-benzyloxyacetamide

[0498] The titled compound (4.17 g) was obtained by the same method asin the Step 1 in the Example 1 by using2-benzyloxy-4′-n-butoxy-N-methylacetanilide (3.27 g).

[0499] Step 2

[0500] Synthesis ofN-(4-n-butoxyphenyl)-N-methyl-2-hydroxy-2-(4-hydroxypiperidin-4-yl)acetamide

[0501] The titled compound (2.46 g) was obtained by the same method asin the Step 1 in the Example 38 by using the compound (4.0 g) obtainedin the Step 1.

[0502] Step 3

[0503] Synthesis ofN-(4-n-butoxyphenyl)-N-methyl-2-hydroxy-2-[4-hydroxy-1-(2-phenylethyl)piperidin-4-yl]acetamide

[0504] The titled compound (1.05 g) was obtained by the same method asin the Step 1 in the Example 34 by using the compound (1.2 g) obtainedin the Step 2 and phenethyl bromide (0.79 g).

[0505] Step 4

[0506] Synthesis of4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]-1-hydroxyethyl]-1-(2-phenylethyl)-piperidin-4-ol

[0507] The titled compound (0.84 g) was obtained by the same method asin the Step 2 in the Example 1 by using the compound (1.0 g) obtained inthe Step 3.

Example 52

[0508] Synthesis of4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]-1-methoxyethyl]-1-[2-(4-fluorophenyl)ethyl]piperidin-4-ol

[0509] Step 1

[0510] Synthesis ofN-(4-n-butoxyphenyl)-N-methyl-2-(4-hydroxypiperidin-4-yl)-2-methoxyacetamide

[0511] The titled compound (0.58 g) was obtained by the same method asin the Step 1 in the Example 19 by using the compound (0.74 g) obtainedin the Step 1 in the Example 11.

[0512] Step 2

[0513] Synthesis ofN-(4-n-butoxyphenyl)-N-methy-2-[1-[2-(4-fluorophenyl)ethyl]-4-hydroxypiperidin-4-yl]-2-methoxyacetamide

[0514] Potassium carbonate (0.34 g) and sodium iodide (61 mg) were addedto an anhydrous dimethylformamide solution (7 mL) of the compound (0.57g) obtained in the Step 1 and 2-(4-fluorophenyl)ethylchloride (0.39 g),and the mixture was stirred at 80 to 95° C. for 5 hours. After allowingto cool, the reaction mixture was poured into ice-water and wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, dried over anhydrous sodium sulfate, and thesolvent was distilled off under a reduced pressure. The residue obtainedwas purified with silica gel chromatography (elution solvent; ethylacetate:methanol=49:1 to 4:1) to obtain the titled compound (0.56 g).

[0515] Step 3

[0516] Synthesis of4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]-1-methoxyethyl]-1-[2-(4-fluorophenyl)ethyl]piperidin-4-ol

[0517] The titled compound (0.43 g) was obtained by the same method asin the Step 2 in the Example 1 by using the compound (0.55 g) obtainedin the Step 2.

Example 53

[0518] Synthesis of4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]-1-hydroxyethyl]-1-[2-(4-fluorophenyl)ethyl]piperidin-4-ol

[0519] Step 1

[0520] Synthesis ofN-(4-n-butoxyphenyl)-N-methyl-2-[4-hydroxy-1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl]-2-hydroxyacetamide

[0521] The titled compound (0.71 g) was obtained by the same method asin the Step 2 in the Example 52 by using the compound (0.62 g) obtainedin the Step 2 in the Example 51.

[0522] Step 2

[0523] Synthesis of4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]-1-hydroxyethyl]-1-[2-(4-fluorophenyl)ethyl]piperidin-4-ol

[0524] The titled compound (0.54 g) was obtained by the same method asin the Step 2 in the Example 1 by using the compound (0.70 g) obtainedin the Step 1.

Example 54

[0525] Synthesis of4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]-ethyl]-1-(2-phenyl-2-hydroxyethyl)piperidin-4-ol

[0526] Sodium borohydride (54 mg) was added to a methanol solution (5mL) of the compound (0.60 g) obtained in the Example 36 underice-cooling, and the solution was stirred for 1 hour. Water was added tothe reaction solution and extracted with ethyl acetate. The organiclayer was washed with water and saturated brine and, after drying overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. The residue obtained was crystallized fromether-hexane to obtain the titled compound (0.43 g).

[0527] The following compound was synthesized by the same method as inthe Example 54.

Example 55

[0528]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-[2-(4-fluorophenyl)-2-hydroxyethyl]piperidin-4-ol

Example 56

[0529] Synthesis of4-[2-[N-acetyl-N-(4-n-butoxyphenyl)amino]-ethyl]-1-benzylpiperidin-4-ol

[0530] The titled compound (1.85 g) was obtained by the same method asin the Step 1 in the Example 33 by using the compound (2.0 g) obtainedin the Step 2 in the Example 13 and acetic acid (0.36 mL).

Example 57

[0531]4-[2-[N-acetyl-N-(4-n-butoxyphenyl)amino]ethyl]-1-[2-(4-fluorophenyl)ethyl]piperidin-4-ol

Example 58

[0532] Synthesis of1-benzyl-4-methoxy-4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]piperidine

[0533] Step 1

[0534] Synthesis ofN-(4-n-butoxyphenyl)-N-methyl-2-(1-tert-butoxycarbonyl-4-hydroxypiperidin-4-yl)acetamide

[0535] The titled compound (7.8 g) was obtained by the same method as inthe Step 1 in the Example 1 by using1-tert-butoxycarbonylpiperidin-4-one (4.5 g) and4′-n-butoxy-N-methylacetanilide (5.0 g).

[0536] Step 2

[0537] Synthesis ofN-(4-n-butoxyphenyl)-N-methyl-2-(1-tert-butoxycarbonyl-4-methoxypiperidin-4-yl)acetamide

[0538] Sodium hydride (60% dispersion in oil; 0.29 g) was added to ananhydrous dimethylformamide solution (10 mL) of the compound (2.0 g)obtained in the Step 1 under ice-cooling, and the mixture was stirredfor 1 hour. Then, methyl iodide (0.6 mL) was added and the mixture wasstirred for 30 minutes, followed by additional stirring at roomtemperature for 3 hours. The reaction mixture was poured into water andextracted with ethyl acetate. The organic layer was washed with waterand saturated brine. After drying the organic layer over anhydroussodium sulfate, the solvent was distilled off under reduced pressure.The residue obtained was recrystallized from ether-hexane to obtain thetitled compound (0.89 g).

[0539] Step 3

[0540] Synthesis ofN-(4-n-butoxyphenyl)-N-methyl-2-(4-methoxypiperidin-4-yl)acetamide

[0541] Trifluoroacetic acid (3 mL) was ice-cooled, added with thecompound (0.80 g) obtained in the Step 2 and stirred for 30 minutes. Thereaction solution was concentrated under reduced pressure, and 1Naqueous sodium hydroxide solution was added to the residue, followed byextraction with ethyl acetate. The organic layer was dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. The residue obtained was purified by silica gel columnchromatography [Chromatorex NH™) (elution solvent:methylenechloride:methanol=49:1 to 9:1) to give the titled compound (0.53 g).

[0542] Step 4

[0543] Synthesis ofN-(4-n-butoxyphenyl)-N-methyl-2-(1-benzyl-4-methoxypiperidin-4-yl)acetamide

[0544] The titled compound (0.43 g) was obtained by the same method asin the Step 2 in the Example 19 by using the compound (0.50 g) obtainedin the Step 3 and benzaldehyde (0.21 g).

[0545] Step 5

[0546] Synthesis of1-benzyl-4-methoxy-4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]piperidine

[0547] The titled compound (0.36 g) was obtained by the same method asin the Step 2 in the Example 1 by using the compound (0.42 g) obtainedin the Step 4.

Example 59

[0548] Synthesis of1-benzyl-4-[N-(4-n-butoxyphenyl)-N-methylaminomethyl]piperidin-4-ol

[0549] Activated neutral aluminum oxide 90 (activity I, made by MerckCo.) (5 g) was added to a diethyl ether solution (10 mL) of1-benzylpiperidin-4-spiro-2′-oxirane (0.50 g) and4-butoxy-N-methylaniline (0.53 g) and stirred at room temperatureovernight. Methanol (20 mL) was added to the reaction solution andstirred at room temperature for 2 hours. The reaction solution wasfiltered, and the filtrate was concentrated under reduced pressure. Theresidue obtained was purified by silica gel column chromatography(elution solvent; ethyl acetate) to obtain the titled compound (0.71 g).

[0550] The following compounds were synthesized by the same methods asin the Step 2 in the Example 19.

Example 60

[0551]4-[2-[N-(4-n-butoxypehyl)-N-methylamino]ethyl]-1-(2-fluorophenylmethyl)piperidin-4-ol

Example 61

[0552]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(3-methylphenylmethyl)piperidin-4-ol

Example 62

[0553]4-[2-[N-(4-n-butoxypehyl)-N-methylamino]ethyl]-1-(2-methylphenylmethyl)piperidin-4-ol

Example 63

[0554]4-[2-[N-(4-n-butoxypehyl)-N-methylamino]ethyl]-1-(3-fluoro-4-methoxyphenylmethyl)piperidin-4-ol

[0555] The following compounds were synthesized by the same methods asin the Steps 1 and 2 in the Example 1.

Example 64

[0556]1-benzyl-4-[2-[N-methyl-N-[4-(2-methyl-2-butoxy)phenyl]-amino]ethyl]piperidin-4-ol

[0557] Step 1

[0558]N-methyl-N-[4-(2-methyl-2-butoxy)phenyl]-2-(1-benzyl-4-hydroxypiperidin-4-yl)acetamide

[0559] Step 2

[0560]1-benzyl-4-[2-[N-methyl-N-[4-(2-methyl-2-butoxy)phenyl]amino]ethyl]piperidin-4-ol

Example 65

[0561]1-benzyl-4-[2-[N-(4-n-butoxy-3-hydroxyphenyl)-N-methylamino]ethyl]piperidin-4-ol

[0562] Step 1

[0563]N-[4-n-butoxy-3-(methoxymethyloxy)phenyl]-N-methyl-2-(1-benzyl-4-hydroxypiperidin-4-yl)acetamide

[0564] Step 2

[0565]1-benzyl-4-[2-[N-(4-n-butoxy-3-hydroxyphenyl)-N-methylamino]ethyl]piperidin-4-ol

Example 66

[0566]1-benzyl-4-[2-[N-(4-n-butoxy-2-fluorophenyl)-N-methylamino]ethyl]piperidin-4-ol

[0567] Step 1

[0568]N-(4-n-butoxy-2-fluorophenyl)-N-methyl-2-(1-benzyl-4-hydroxypiperidin-4-yl)acetamide

[0569] Step 2

[0570]1-benzyl-4-[2-[N-(4-n-butoxy-2-fluorophenyl)-N-methylamino]ethyl]piperidin-4-ol

Example 67

[0571]1-benzyl-4-[2-[N-(4-n-butoxyphenyl)-N-isopropylamino]-ethyl]piperidin-4-ol

[0572] Step 1

[0573]N-(4-n-butoxyphenyl)-N-isopropyl-2-(1-benzyl-4-hydroxypiperidin-4-yl)acetamide

[0574] Step 2

[0575]1-benzyl-4-[2-[N-(4-n-butoxyphenyl)-N-isopropylamino]ethyl]piperidin-4-ol

[0576] The following compounds were synthesized by the same method as inthe Step 2 in the Example 14.

Example 68

[0577]1-benzyl-4-[2-[N-methyl-N-[4-(3-pentyloxy)phenyl]-amino]ethyl]piperidin-4-ol

Example 69

[0578]1-benzyl-4-[2-[N-methyl-N-[4-(3-methylbutoxy)phenyl]-amino]ethyl]piperidin-4-ol

Example 70

[0579]1-benzyl-4-[2-[N-[4-(2-cyclopropylethyloxy)phenyl]-N-methylamino]ethyl]piperidin-4-ol

Example 71

[0580]1-benzyl-4-[2-[N-[4-(3-butenyloxy)phenyl]-N-methylamino]ethyl]piperidin-4-ol

Example 72

[0581] Synthesis of1-(4-chorophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

[0582] Step 1

[0583] Synthesis of4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

[0584] The titled compound (0.31 g) was obtained by the same method asin the Step 1 in the Example 38 by using the compound (0.45 g) obtainedin the Step 2 in the Example 4.

[0585] Step 2

[0586] Synthesis of1-(4-chlorophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

[0587] The titled compound (0.14 g) was obtained by the same method asin the Step 2 in the Example 19 by using the compound (0.15 g) obtainedin the Step 1 and 4-chlorobenzaldehyde (0.14 g).

[0588] The following compounds were synthesized by the same method as inthe Step 2 in the Example 72.

Example 73

[0589]1-(4-bromophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

Example 74

[0590]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-[4-(trifluoromethyl)phenylmethyl]piperidin-4-ol

Example 75

[0591]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethylj-1-[(4-isopropylphenyl)methyl]piperidin-4-ol

Example 76

[0592]1-(4-methoxyphenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

Example 77

[0593]1-(3-methoxyphenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

Example 78

[0594]1-(4-fluorophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

Example 79

[0595]1-(4-cyanophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

Example 80

[0596]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-(2-naphthylmethyl)piperidin-4-ol

Example 81

[0597]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-[(4-isopropoxyphenyl)methyl]piperidin-4-ol

Example 82

[0598]1-(2-bromophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

Example 83

[0599]1-(3-bromophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

Example 84

[0600]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-(4-nitrophenylmethyl)piperidin-4-ol

Example 85

[0601]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-[3-(trifluoromethyl)phenylmethyl]piperidin-4-ol

Example 86

[0602]1-[4-(methoxycarbonyl)phenylmethyl]-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

Example 87

[0603]1-(2,4-difluorophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

Example 88

[0604]1-[4-fluoro-3-(trifluoromethyl)phenylmethyl]-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

Example 89

[0605]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-(4-trifluoromethoxyphenylmethyl)piperidin-4-ol

Example 90

[0606]1-(2-fluoro-4-isopropoxyphenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

Example 91

[0607]1-(4-biphenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

Example 92

[0608]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-(4-phenoxyphenylmethyl)piperidin-4-ol

Example 93

[0609]1-(4-bromo-2-fluorophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

Example 94

[0610]1-(3-fluorophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

Example 95

[0611]1-(2-fluorophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

Example 96

[0612]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-(3-trifluoromethoxyphenylmethyl)piperidin-4-ol

Example 97

[0613]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1(2-trifluoromethoxyphenylmethyl)piperidin-4-ol

Example 98

[0614]1-(3-chlorophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

Example 99

[0615]1-(2-chlorophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

Example 100

[0616]1-(3-cyanophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

Example 101

[0617]1-(2-cyanophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

Example 102

[0618]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-[2-(trifluoromethyl)phenylmethyl]piperidin-4-ol

Example 103

[0619]1-(2-methoxyphenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

Example 104

[0620]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-(3-nitrophenylmethyl)piperidin-4-ol

Example 105

[0621]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1(2-nitrophenylmethyl)piperidin-4-ol

Example 106

[0622]1-[4-(ethoxycarbonyl)phenylmethyl]-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

Example 107

[0623]4-[2-[N-methyl-N-(4-isopropoxyphenyl]amino]ethyl]-1-(2-thienylmethyl)piperidin-4-ol

Example 108

[0624]4-[2-[N-methyl-N-(4-isopropoxyphenyl]amino]ethyl]-1-(3-thienylmethyl)piperidin-4-ol

Example 109

[0625]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-[4-(methylthio)phenylmethyl]piperidin-4-ol

Example 110

[0626]1-[2-(methoxycarbonyl)phenylmethyl]-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

Example 111

[0627]1-[3-(methoxycarbonyl)phenylmethyl]-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

Example 112

[0628]1-(3-furylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

Example 113

[0629]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-[4-(isopropoxycarbonyl)phenylmethyl]piperidin-4-ol

Example 114

[0630]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-[4-(n-propoxycarbonyl)phenylmethyl]piperidin-4-ol

Example 115

[0631] Synthesis of4-[2-[N-methyl-N-(4-isopropoxyphenyl)-amino]ethyl]-1-(2-phenoxyethyl)piperidin-4-ol

[0632] 2-Phenoxyethyl bromide (0.2 g), potassium carbonate (0.14 g) andsodium iodide (15 mg) were added to a dimethylformamide solution (5 mL)of the compound (0.29 g) obtained in the Step 1 in the Example 72 andstirred at 100° C. for 2 hours. The reaction solution was poured intoice-water and extracted with ethyl acetate. The organic layer was washedwith water and extracted with 1N aqueous hydrochloric acid. The aqueouslayer was adjusted to pH 9 with sodium hydrogen carbonate, and wasextracted with ethyl acetate. The organic layer obtained was washed withwater and saturated brine, dried over anhydrous sodium sulfate, and thesolvent was distilled off under a reduced pressure. The residue obtainedwas purified by silica gel column chromatography (elution solvent;methylene chloride:methanol=94:6 to 85:15) to obtain the titled compound(0.38 g).

[0633] The following compounds were synthesized by the same method as inthe Example 115.

Example 116

[0634]1-[2-(4-fluorophenoxy)ethyl]-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

Example 117

[0635]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-(3-phenylpropyl)piperidin-4-ol

Example 118

[0636]1-(3-biphenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

Example 119

[0637]1-(2-biphenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

Example 120

[0638] Synthesis of1-[2-fluoro-4-(trifluoromethyl)phenylmethyl]-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

[0639] Step 1

[0640] Synthesis of1-[2-fluoro-4-(trifluoromethyl)benzoyl]-4-[2-[N-methyl-N-(4-isopropoxyphenyl)-amino]ethyl]piperidin-4-ol

[0641] The titled compound (0.4 g) was obtained by the same method as inthe Step 1 in the Example 33 by using the compound (0.3 g) obtained inthe Step 1 in the Example 72.

[0642] Step 2

[0643] Synthesis of1-[2-fluoro-4-(trifluoromethyl)-phenylmethyl]-4-[2-[N-methyl-N-(4-isopropoxyphenyl)-amino]ethyl]piperidin-4-ol

[0644] The titled compound (0.35 g) was obtained by the same method asin the Step 2 in the Example 1 by using the compound (0.39 g) obtainedin the Step 1.

Example 121

[0645] Synthesis of4-[2-[N-methyl-N-(4-ethoxyphenyl)amino]ethyl]-1-[4-(trifluoromethyl)phenylmethyl]piperidin-4-ol

[0646] Step 1

[0647] Synthesis of4-[2-[N-methyl-N-(4-ethoxyphenyl)-amino]ethyl]piperidin-4-ol

[0648] The titled compound (4.10 g) was obtained by the same method asin the step 1 in the example 38 using the compound (5.48 g) obtained inthe Step 2 in the Example 2.

[0649] Step 2

[0650] Synthesis of4-[2-[N-methyl-N-(4-ethoxyphenyl)-amino]ethyl]-1-[4-(trifluoromethyl)phenylmethyl]-piperidin-4-ol

[0651] The titled compound (0.61 g) was obtained by the same method asin the Step 2 in the Example 19 by using the compound (0.42 g) obtainedin the Step 1.

Example 122

[0652] Synthesis of1-[4-(methoxycarbonyl)phenylmethyl]-4-[2-[N-methyl-N-(3-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

[0653] Step 1

[0654] Synthesis ofN-methyl-N-(3-isopropoxyphenyl)-2-(1-benzyl-4-hydroxypiperidin-4-yl)acetamide

[0655] The titled compound (7.39 g) was obtained by the same method asin the Step 1 in the Example 1 by using3′-isopropoxy-N-methylacetanilide (5.50 g).

[0656] Step 2

[0657] Synthesis of1-benzyl-4-[2-[N-methyl-N-(3-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

[0658] An anhydrous tetrahydrofuran solution (28 mL) of the compound(7.00 g) obtained in the step 1 was cooled with ice-water under nitrogenatmosphere. A tetrahydrofuran solution of borane-tetrahydrofuran complex(1M; 70.7 mL) was added little by little. After completing the addition,the solution was heated under reflux for 2 hours. Methanol (20 mL) wasadded little by little under cooling with ice-water, and the solutionwas adjusted to below pH 1 by adding 10% hydrochloric acid-methanolsolution(20 mL), followed by heat under reflux for 1.5 hour. Afterallowing the reaction solution to cool, the solvent was distilled off,and the residue was dissolved in 1N hydrochloric acid. After washingwith ether, the aqueous layer was adjusted to pH 9 by adding potassiumcarbonate and extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous sodium sulfate, and thesolvent was distilled off under reduced pressure. The residue obtainedwas purified by silica gel column chromatography [Chromatorex NH™](elution solvent; ethyl acetate:hexane=1:4 to 2:3) to obtain the titledcompound (6.52 g).

[0659] Step 3

[0660] Synthesis of4-[2-[N-methyl-N-(3-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

[0661] The titled compound (4.63 g) was obtained by the same method asin the Step 1 in the Example 38 by using the compound (6.00 g) obtainedin the Step 2.

[0662] Step 4

[0663] Synthesis of1-[4-(methoxycarbonyl)phenylmethyl]-4-[2-[N-methyl-N-(3-isopropoxyphenyl)amino]ethyl]-piperidin-4-ol

[0664] The titled compound (0.74 g) was obtained by the same method asin the Step 2 in the Example 19 by using the compound (0.50 g) obtainedin the Step 3 and 4-(methoxycarbonyl)benzaldehyde (0.56 g).

[0665] The following compounds were synthesized by the same method as inthe Steps 1 to 4 in the Example 122.

Example 123

[0666]1-[4-(methoxycarbonyl)phenylmethyl]-4-[2-[N-methyl-N-(2-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

[0667] Step 1

[0668]N-methyl-N-(2-isopropoxyphenyl)-2-(1-benzyl-4-hydroxypiperidin-4-yl)acetamide

[0669] Step 2

[0670]1-benzyl-4-[2-[N-methyl-N-(2-isopropoxyphenyl)-amino]ethyl]piperidin-4-ol

[0671] Step 3

[0672] 4-[2-[N-methyl-N-(2-isopropoxyphenyl)-amino]ethyl]piperidin-4-ol

[0673] Step 4

[0674]1-[4-(methoxycarbonyl)phenylmethyl]-4-[2-[N-methyl-N-(2-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

Example 124

[0675] Synthesis of4-[2-[N-(4-isopropoxyphenyl)amino]ethyl]-1-[4-(methoxycarbonyl)phenylmethyl]piperidin-4-ol

[0676] Step 1

[0677] Synthesis ofN-(4-isopropoxyphenyl)-2-(1-benzyl-4-hydroxypiperidin-4-yl)acetamide

[0678] Sodium hydride (60% dispersion in oil; 1.99 g) was added to ananhydrous tetrahydrofuran solution (80 mL) of 4′-isopropoxyacetanilide(8.0 g) under nitrogen atmosphere while cooling with ice-water, followedby stirring at the intact temperature for 1 hour. The reaction solutionwas cooled to −50° C. and added with an anhydrous tetrahydrofuransolution (80 mL) of lithium diisopropylamide prepared fromdiisopropylamine (11.6 mL) and n-butyl lithium (1.6M hexane solution;51.8 mL), followed by stirring at −50 to −30° C. for 1 hour. Ananhydrous tetrahydrofuran solution (40 mL) of 1-benzylpiperidin-4-one(7.83 g) was added to the reaction solution above at −30° C., and themixture was stirred −30° C. for 30 minutes, and under cooling withice-water for 2 hours. The reaction solution was poured into ice-water,and the aqueous solution was extracted with ethyl acetate. The organiclayer was sequentially washed with water and saturated brine, dried overanhydrous sodium sulfate, and the solution was distilled off underreduced pressure. The residue obtained was purified by silica gel columnchromatography (elution solvent; methylene chloride:methanol=90:10 to75:25) to obtain the titled compound (10.3 g).

[0679] Step 2

[0680] Synthesis of1-benzyl-4-[2-[N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

[0681] The titled compound (4.4 g) was obtained by the same method as inthe Step 2 in the Example 122 by using the compound (9.9 g) in the Step1.

[0682] Step 3

[0683] Synthesis of4-[2-[N-(4-isopropoxyphenyl)amino]-ethyl]piperidin-4-ol

[0684] The titled compound (3.2 g) was obtained by the same method as inthe Step 1 in the Example 38 by using the compound (4.3 g) in the Step2.

[0685] Step 4

[0686] Synthesis of4-[2-[N-(4-isopropoxyphenyl)amino]-ethyl]-1-[4-(methoxycarbonyl)phenylmethyl]piperidin-4-ol

[0687] The titled compound (0.23 g) was obtained by the same method asin the Step 2 in the Example 19 by using the compound (0.42 g) in theStep 3 and 4-(methoxycarbonyl)benzaldehyde (0.25 g).

Example 125

[0688] Synthesis of4-[2-[N-(4-isopropoxyphenyl)amino]ethyl]-1-[4-(trifluoromethyl)phenylmethyl]piperidin-4-ol

[0689] The titled compound (0.21 g) was obtained by the same method asin the Step 2 in the Example 19 by using the compound (0.42 g) in theStep 3 in the Example 124 and 4-(trifluoromethyl)-benzaldehyde (0.26 g).

Example 126

[0690] Synthesis of4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]-1-hydroxyethyl]-1-[4-trifluoromethyl)-phenylmethyl]piperidin-4-ol

[0691] Step 1

[0692] Synthesis ofN-methyl-N-(4-isopropoxyphneyl)-2-(1-benzyl-4-hydroxypiperidin-4-yl)-2-benzyloxyacetamide

[0693] The titled compound (7.35 g) was obtained by the same method asin the Step 1 in the Example 1 by using2-benzyloxy-4′-isopropoxy-N-methylacetanilide (5.20 g).

[0694] Step 2

[0695] Synthesis ofN-methyl-N-(4-isopropoxyphneyl)-2-hydroxy-2-(4-hydroxypiperidin-4-yl)acetamide

[0696] The titled compound (2.80 g) was obtained by the same method asin the Step 1 in the Example 19 by using the compound (7.35 g) obtainedin the Step 1.

[0697] Step 3

[0698] Synthesis of4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]l1-hydroxyethyl]piperidin-4-ol

[0699] The titled compound (0.5 g) was obtained by the same method as inthe Step 2 in the Example 122 by using the compound (0.7 g) obtained inthe Step 2.

[0700] Step 4

[0701] Synthesis of4-[2-[N-methyl-N-(4-isopropoxphenyl)amino]-1-hydroxyethyl]-1-[4-(trifluoromethyl)phenylmethyl]piperidin-4-ol

[0702] The titled compound (0.56 g) was obtained by the same method asin the Step 2 in the Example 19 by using the compound (0.46 g) obtainedin the Step 3 and 4-(trifluoromethyl) benzaldehyde (0.52 g).

Example 127

[0703] Synthesis of4-methoxy-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-[4-(trifluoromethyl)-phenylmethyl]piperidine

[0704] Step 1

[0705] Synthesis ofN-methyl-N-(4-isopropoxyphenyl)-2-(1-tert-butoxycarbonyl-4-hydroxypiperidin-4-yl)acetamide

[0706] The titled compound (9.5 g) was obtained by the same method as inthe Step 1 in the Example 1 by using1-tert-butoxycarbonylpiperidin-4-one (6.7 g) and4′-isopropoxy-N-methylacetanilide (7.0 g).

[0707] Step 2

[0708] Synthesis ofN-methyl-N-(4-isopropoxyphenyl)-2-(1-tert-butoxycarbonyl-4-methoxypiperidin-4-yl)acetamide

[0709] The titled compound (5.22 g) was obtained by the same method asin the Step 2 in the Example 58 by using the compound (8.50 g) obtainedin the Step 1.

[0710] Step 3

[0711] Synthesis of4-methoxy-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidine

[0712] The titled compound (2.52 g) was obtained by the same method asin the Step 2 of the Example 122 by using the compound (4.7 g) obtainedin the Step 2.

[0713] Step 4

[0714] Synthesis of4-methoxy-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-[4-(trifluormethyl)-phenylmethyl]piperidine

[0715] The titled compound (0.59 g) was obtained by the same method asin the Step 2 in the Example 19 by using the compound (0.46 g) obtainedin the step 3 and 4-(trifluoromethyl)benzaldehyde (0.52 g).

Example 128

[0716] Synthesis of4-methoxy-1-[4-(methoxycarbonyl)phenylmethyl]-4-[2-[N-methyl-N-(4-isopropoxyphenyl)-amino]ethyl]piperidine

[0717] The titled compound (0.46 g) was obtained by the same method asin the Step 2 in the Example 19 by using the compound (0.40 g) obtainedin the Step 3 in the Example 127 and 4-(methoxycarbonyl)benzaldehyde(0.43 g).

Example 129

[0718] Synthesis of4-[N-methyl-N-(4-isopropoxypheny)-aminomethyl]-1-[4-(trifluoromethyl)phenylmethyl]piperidin-4-ol

[0719] Step 1

[0720] Synthesis of1-benzyl-4-[N-methyl-N-(4-isopropoxypheny)aminomethyl]piperidin-4-ol

[0721] The titled compound (2.43 g) was obtained by the same method asin the Example 59 by using N-methyl-4-isopropoxyaniline (3.37 g)

[0722] Step 2

[0723] Synthesis of4-[N-methyl-N-(4-isopropoxypheny)-aminomethyl]piperidin-4-ol

[0724] The titled compound (1.81 g) was obtained by the same method asin the Step 1 in the Example 38 by using the compound (2.40 g) obtainedin the Step 1.

[0725] Step 3

[0726] Synthesis of4-[N-methyl-N-(4-isopropoxypheny)-aminomethyl]-1-[4-(trifluoromethyl)phenylmethyl]-piperidin-4-ol

[0727] The titled compound (0.39 g) was obtained by the same method asin the Step 2 in the Example 19 by using the compound (0.30 g) obtainedin the Step 2 and 4-(trifluoromethyl)benzaldehyde (0.38 g).

Example 130

[0728] Synthesis of1-[4-(methoxycarbonyl)phenylmethyl]-4-[N-methyl-N-(4-isopropoxyphenyl)aminomethyl]piperidin-4-ol

[0729] The titled compound (0.34 g) was obtained by the same method asin the Step 2 in the Example 19 by using the compound (0.30 g) obtainedin the Step 2 of the Example 129 and 4-(methoxycarbonyl)benzaldehyde(0.35 g).

Example 131

[0730] Synthesis of1-diphenylmethyl-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

[0731] Diphenylmethyl bromide (0.27 g), triethylamine (0.11 g) andsodium iodide (15 mg) were added to a tetrahydrofuran solution (4 mL) ofthe compound (0.30 g) obtained in the Step 1 in the Example 72 andheated under reflux for 11 hours under nitrogen atmosphere. The reactionsolution was cooled, added with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layerwas washed with saturated brine, dried over anhydrous sodium sulfate,and the solvent was distilled off under reduced pressure. The residueobtained was purified by silica gel column chromatography (elutionsolvent; hexane:ethyl acetate=7:3) to obtain the titled compound (0.23g).

[0732] The following compounds were synthesized by the same method as inthe Example 131.

Example 132

[0733]1-bis(4-fluorophenyl)methyl-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

Example 133

[0734]1-diphenylmethyl-4-[2-[N-(4-ethoxyphenyl)-N-methylamino]ethyl]piperidin-4-ol

Example 134

[0735]1-diphenylmethyl-4-[2-[N-methyl-N-(3-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

Example 135

[0736]1-diphenylmethyl-4-[2-[N-methyl-N-(2-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

Example 136

[0737]1-diphenylmethyl-4-[2-[N-(4-isopropoxyphenyl)-amino]ethyl]piperidin-4-ol

Example 137

[0738]1-diphenylmethyl-4-methoxy-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidine

Example 138

[0739]1-diphenylmethyl-4-[N-methyl-N-(4-isopropoxyphenyl)-aminomethyl]piperidin-4-ol

Example 139

[0740] Synthesis of1-benzyl-4-[2-[N-(4-n-butoxyphenyl)-N-ethylamino]ethyl]piperidin-4-ol

[0741] The titled compound (0.16 g) was obtained by the same method asin the step 2 in the example 19 using the compound (0.15 g) obtained inthe step 2 in the example 13 and an excess amount of acetaldehyde.

Example 140

[0742] Synthesis of1-(4-cyano-2-fluorophenylmehtyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

[0743] Copper (I) cyanide (0.1 g) was added to an anhydrousdimethylformamide solution (2 mL) of the compound (0.4 g) obtained inthe Example 93 and heated under reflux for 10 hours under nitrogenatmosphere. After the reaction solution was cooled to room temperature,a solution of ethylene diamine and water (3:7) was added to the reactionsolution and stirred at 50° C. under heating. Then, the reactionsolution was extracted with ethyl acetate, and the organic layerobtained was sequentially washed with water and saturated brine. Theorganic phase was dried over anhydrous sodium sulfate, and the solventwas distilled off under reduced pressure. The residue was purified bysilica gel column chromatography [Chromatorex NH™] (elution solvent;ethyl acetate:hexane=1:3) to obtain the titled compound (0.12 g).

Example 141

[0744] Synthesis of1-(4-acetylphenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxypheny)amino]ethyl]piperidin-4-ol

[0745] An anhydrous tetrahydrofuran solution (5 mL) of the compound(0.50 g) obtained in the example 79 was added dropwise to an ethersolution (1M; 6.1 mL) of methyl lithium while cooling with ice-water,and the mixture was stirred for 40 minutes under cooling with ice-water.Then, sulfuric acid (3M; 2.5 mL) was added to the reaction solutionwhile cooling with ice-water, followed by stirring at room temperaturefor 20 minutes. The reaction solution was made alkaline by addingsaturated aqueous sodium bicarbonate solution, and was extracted withethyl acetate. The organic layer was washed with saturated brine, driedover anhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (elution solvent; methylene chloride:methanol=20:1) toobtain the titled compound (0.38 g).

Example 142

[0746] Synthesis of4-[2-[N-methyl-N-(4-isopropoxyphenyl)-amino]ethyl]-1-[4-(trifluoroacetylamino)phenylmethyl]-piperidin-4-ol

[0747] Step 1

[0748] Synthesis of1-(4-aminophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol

[0749] The compound (0.35 g) obtained in the Example 84 was dissolved inacetic acid (4 mL), and ion powder (0.15 g) was added to the solution,followed by stirring at 70 to 80° C. for 1.5 hours. Insoluble materialswere removed by filtration, and the filtrate was concentrated underreduced pressure. The residue obtained was dissolved in methylenechloride, and the solution was sequentially washed with saturatedaqueous sodium bicarbonate solution and saturated brine. After dryingthe organic layer obtained over anhydrous sodium sulfate, the solventwas distilled off under reduced pressure. The residue obtained waspurified by silica gel column chromatography [Cromatorex NH™] (elutionsolvent; ethyl acetate:hexane=1:2 to 2:1) to obtain the titled compound(0.23 g).

[0750] Step 2

[0751] Synthesis of4-[2-[N-methyl-N-(4-isopropoxyphenyl)-amino]ethyl]-1-[4-(trifluoroacetylamino)-phenylmethyl]piperidin-4-ol

[0752] The compound (0.31 g) obtained in the Step 1 and triethylamine(0.12 mL) was dissolved in methylene chloride (5 mL), andtrifluoroacetic anhydride (0.12 mL) was added dropwise with stirringunder cooling with ice-water. After stirring the reaction solution for30 minutes at the same temperature and for 30 minutes at roomtemperature, water (2 mL) was added while cooling with ice-water again.Saturated aqueous sodium bicarbonate was added to the reaction solution,and the mixed solution was extracted with methylene chloride. Theorganic layer was washed with saturated brine, dried over anhydroussodium sulfate, and the solvent was distilled off under reducedpressure. The residue obtained was purified by silica gel columnchromatography (elution solvent; methylene chloride:methanol=95:5 to85:15) to obtain the titled compound (0.27 g).

Example 143

[0753] Synthesis of1-(4-carboxyphenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ollithium salt

[0754] The compound (0.44 g) obtained in the Example 86 was dissolved inmethanol (20 mL), and an aqueous solution (2 mL) of lithium hydroxidemonohydrate (42 mg) was added followed by heat under reflux for 18hours. The solvent was distilled off under reduced pressure, ether wasadded to the residue, and the precipitated solid was filtered off toobtain the titled compound (0.35 g).

Example 144

[0755] Preparation of1-benzyl-4-[2-[N-(4-methoxyphenyl)-N-methylamino]ethyl]piperidin-4-oldihydrochloride

[0756] After adding a 10% methanol solution (2 mL) of hydrochloric acidto a methanol solution (5 mL) of the compound (1.0 g) obtained in theStep 2 in the Example 1, the solvent was distilled off under reducedpressure. The titled compound (0.98 g) was obtained by recrystallizationof the residue obtained from ether.

[0757] The following hydrochlorides were obtained by the same method asin the Example 144.

Example 145

[0758]1-benzyl-4-[2-[N-(4-ethoxyphenyl)-N-methylamino]ethyl]-piperidin-4-oldihydrochloride

Example 146

[0759]1-benzyl-4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]piperidin-4-oldihydrochloride

Example 147

[0760]1-benzyl-4-[2-[N-methyl-N-(4-isopropoxyphenyl)-amino]ethyl]piperidin-4-oldihydrochloride

Example 148

[0761]1-benzyl-4-[2-[N-(4-cyclohexyloxyphenyl)-N-methylamino]ethyl]piperidin-4-oldihydrochloride

Example 149

[0762]1-benzyl-4-[2-[N-methyl-N-(4-phenoxyphenyl)amino]ethyl]-piperidin-4-oldihydrochloride

Example 150

[0763]1-benzyl-4-[2-[N-(3-n-butoxyphenyl)-N-methylamino]-ethyl]piperidin-4-oldihydrochloride

Example 151

[0764]1-benzyl-4-[2-[N-(2-n-butoxyphenyl)-N-methylamino]-ethyl]piperidin-4-oldihydrochloride

Example 152

[0765]1-benzyl-4-[2-[N-(4-n-butoxy-3-fluorophenyl)-N-methylamino]ethyl]piperidin-4-oldihydrochloride

Example 153

[0766]1-benzyl-4-[2-[N-methyl-N-(4-n-propylphenyl)amino]-ethyl]piperidin-4-oldihydrochloride

Example 154

[0767]1-benzyl-4-[2-[N-(4-n-butoxyphenyi)-N-methylamino]-1-methoxyethyl]piperidin-4-oldihydrochloride

Example 155

[0768]1-benzyl-4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]-1-hydroxyethyl]piperidin-4-oldihydrochloride

Example 156

[0769] 1-benzyl-4-[2-[N-(4-n-butoxyphenyl)amino]ethyl]piperidin-4-oldihydrochloride

Example 157

[0770]1-benzyl-4-[2-[N-methyl-N-(4-n-propoxyphenyl)amino]-ethyl]piperidin-4-oldihydrochloride

Example 158

[0771]1-benzyl-4-[2-[N-methyl-N-(4-n-pentyloxyphenyl)amino]-ethyl]piperidin-4-oldihydrochloride

Example 159

[0772]1-benzyl-4-[2-[N-(4-isobutoxyphenyl)-N-methylamino]ethyl]piperidin-4-oldihydrochloride

Example 160

[0773]1-benzyl-4-[2-[N-(4-cyclobutoxyphenyl)-N-methylamino]ethyl]piperidin-4-oldihydrochloride

Example 161

[0774]1-benzyl-4-[2-[N-methyl-N-(4-cyclopropylmethyloxyphenyl)-amino]ethyl]piperidin-4-oldihydrochloride

Example 162

[0775]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(3,4-methylenedioxyphenylmethyl)piperidin-4-oldihydrochloride

Example 163

[0776]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(4-chlorophenylmethyl)piperidin-4-oldihydrochloride

Example 164

[0777]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-[4-(trifluoromethyl)phenylmethyl]piperidin-4-oldihydrochloride

Example 165

[0778]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(4-cyanophenylmethyl)piperidin-4-oldihydrochloride

Example 166

[0779]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(4-methoxycarbonylphenylmethyl)piperidin-4-oldihydrochloride

Example 167

[0780]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-[4-(dimethylamino)phenylmethyl]piperidin-4-oltrihydrochloride

Example 168

[0781]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(4-hydroxyphenylmethyl)piperidin-4-oldihydrochloride

Example 169

[0782]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1(4-methoxyphenylmethyl)piperidin-4-oldihydrochloride

Example 170

[0783]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(3-methoxyphenylmethyl)piperidin-4-oldihydrochloride

Example 171

[0784]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(2-methoxyphenylmethyl)piperidin-4-oldihydrochloride

Example 172

[0785]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(3-fluorophenylmethyl)piperidin-4-oldihydrochloride

Example 173

[0786]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]l-1(3,4-difluorophenylmethyl)piperidin-4-oldihydrochloride

Example 174

[0787]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(4-methylphenylmethyl)piperidin-4-oldihydrochloride

Example 175

[0788]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]l-1(2,3-dihydro-1H-inden-2-yl)piperidin-4-oldihydrochloride

Example 176

[0789]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-[2-(4-fluorophenyl)ethyl]piperidin-4-oldihydrochloride

Example 177

[0790]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]l-1(4-fluorophenylmethyl)piperidin-4-oldihydrochloride

Example 178

[0791]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(1-phenylethyl)piperidin-4-oldihydrochloride

Example 179

[0792]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-benzoylmethylpiperidin-4-oldihydrochloride

Example 180

[0793]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(4-fluorobenzoylmethyl)piperidin-4-oldihydrochloride

Example 181

[0794]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]-1-methoxyethyl]-1-(2-phenylethyl)piperidin-4-oldihydrochloride

Example 182

[0795]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-[2-(4-methoxyphenyl)ethyl]piperidin-4-oldihydrochloride

Example 183

[0796]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-[2-(2,4-difluorophenyl)ethyl]piperidin-4-oldihydrochloride

Example 184

[0797]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-[2-(3,4-methylenedioxyphenyl)ethyl]piperidin-4-oldihydrochloride

Example 185

[0798]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(3-phenylpropyl)piperidin-4-oldihydrochloride

Example 186

[0799]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(2-phenoxyethyl)piperidin-4-oldihydrochloride

Example 187

[0800]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1(2-phenylethyl)piperidin-4-oldihydrochloride

Example 188

[0801]4-[2-[N-(4-n-butoxyphenyl)amino]ethyl]-1-[2-(4-fluorophenyl)ethyl]piperidin-4-oldihydrochloride

Example 189

[0802]4-[2-[N-(4-cyclobutoxyphenyl)-N-methylamino]ethyl]-1-(2-phenylethyl)piperidin-4-oldihydrochloride

Example 190

[0803]4-[2-[N-(4-cyclobutoxyphenyl)-N-methylamino]ethyl]-1-[2-(4-fluorophenyl)ethyl]piperidin-4-oldihydrochloride

Example 191

[0804]4-[2-[N-(4-cyclobutoxyphenyl)-N-methylamino]ethyl]-1-[2-(2-chlorophenyl)ethyl]piperidin-4-oldihydrochloride

Example 192

[0805]4-[2-[N-[4-n-butoxy-3-(hydroxymethyl)phenyl]-N-methylamino]ethyl]-1-[2-(4-fluorophenyl)ethyl]piperidin-4-oldihydrochloride

Example 193

[0806]4-[2-[N-[4-n-butoxy-2-(hydroxymethyl)phenyl]-N-methylamino]ethyl]-1-[2-(3,4-methylenedioxyphenyl)-ethyl]piperidin-4-oldihydrochloride

Example 194

[0807]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]-1-hydroxyethyl]-1-(2-phenylethyl)piperidin-4-oldihydrochloride

Example 195

[0808]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]-1-methoxyethyl]-1-[2-(4-fluorophenyl)ethyl]piperidin-4-oldihydrochloride

Example 196

[0809]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]-1-hydroxyethyl]-1-[2-(4-fluorophenyl)ethyl]piperidin-4-oldihydrochloride

Example 197

[0810]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(2-phenyl-2-hydroxyethyl)piperidin-4-oldihydrochloride

Example 198

[0811]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-[2-(4-fluorophenyl)-2-hydroxyethyl]piperidin-4-oldihydrochloride

Example 199

[0812]4-[2-[N-acetyl-N-(4-n-butoxyphenyl)amino]ethyl]-1-benzyl-piperidin-4-olmonohydrochloride

Example 200

[0813]4-[2-[N-acetyl-N-(4-n-butoxyphenyl)amino]ethyl]-1-[2-(4-fluorophenyl)ethyl]piperidin-4-olmonohydrochloride

Example 201

[0814]1-benzyl-4-methoxy-4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]piperidinedihydrochloride

Example 202

[0815]1-benzyl-4-[N-(4-n-butoxyphenyl)-N-methylaminomethyl]-piperidin-4-oldihydrochloride

Example 203

[0816]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(2-fluorophenylmethyl)piperidin-4-oldihydrochloride

Example 204

[0817]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(3-methylphenylmethyl)piperidin-4-oldihydrochloride

Example 205

[0818]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]l-1(2-methylphenylmethyl)piperidin-4-oldihydrochloride

Example 206

[0819]4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(3-fluoro-4-methoxyphenylmethyl)piperidin-4-oldihydrochloride

Example 207

[0820] Preparation of1-benzyl-4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]piperidin-4-oldimaleate

[0821] Maleic acid (0.23 g) was added to a 2-propanol solution (10 mL)of the compound (0.40 g) obtained in the Step 2 in the Example 3 anddissolved under heating. After allowing the solution to cool, thecrystals precipitated were collected by filtration and washed with etherto obtain the titled compound (0.59 g).

Example 208

[0822] Preparation of1-benzyl-4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]piperidin-4-olmonomaleate

[0823] Maleic acid (0.lOg) was added to a methanol solution (2 mL) ofthe compound (0.35 g) obtained in the Step 2 in the Example 3. Thetitled compound (0.45 g) was obtained by removing the solvent underreduced pressure.

[0824] The following maleic acid salts were prepared by the same methodas in the Example 208.

Example 209

[0825]4-[2-[N-[4-n-butoxy-2-(hydroxymethyl)phenyl]-N-methylamino]ethyl]-1-[2-(3,4-methylenedioxyphenyl)-ethyl]piperidin-4-olmonomaleate

Example 210

[0826]1-benzyl-4-[N-(4-n-butoxyphenyl)-N-methylamino]-methylpiperidin-4-olmonomaleate

[0827] The following hydrochlorides were prepared by the same method asin the Example 144.

Example 211

[0828]1-benzyl-4-[2-[N-methyl-N-[4-(2-methyl-2-butoxy)phenyl]-amino]ethyl]piperidin-4-oldihydrochloride

Example 212

[0829]1-benzyl-4-[2-[N-(4-n-butoxy-3-hydroxyphenyl)-N-methylamino]ethyl]piperidin-4-oldihydrochloride

Example 213

[0830]1-benzyl-4-[2-[N-(4-n-butoxy-2-fluorophenyl)-N-methylamino]ethyl]piperidin-4-oldihydrochloride

Example 214

[0831]1-benzyl-4-[2-[N-(4-n-butoxyphenyl)-N-isopropylamino]ethyl]piperidin-4-oldihydrochloride

Example 215

[0832]1-benzyl-4-[2-[N-methyl-N-[4-(3-pentyloxy)phenyl]-amino]ethyl]piperidin-4-oldihydrochloride

Example 216

[0833]1-benzyl-4-[2-[N-methyl-N-[4-(3-methylbutoxy)phenyl]-amino]ethyl]piperidin-4-oldihydrochloride

Example 217

[0834]1-benzyl-4-[2-[N-[4-(2-cyclopropylethyloxy)phenyl]-N-methylamino]ethyl]piperidin-4-oldihydrochloride

Example 218

[0835]1-benzyl-4-[2-[N-[4-(3-butenyloxy)phenyl]-N-methylamino]ethyl]piperidin-4-oldihydrochloride

Example 219

[0836]1-(4-chlorophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-oldihydrochloride

Example 220

[0837]1-(4-bromophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-oldihydrochloride

Example 221

[0838]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-[4-(trifluoromethyl)phenylmethyl]piperidin-4-oldihydrochloride

Example 222

[0839]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-[(4-isopropylphenyl)methyl]piperidin-4-oldihydrochloride

Example 223

[0840]1-(4-methoxyphenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-oldihydrochloride

Example 224

[0841]1-(3-methoxyphenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-oldihydrochloride

Example 225

[0842]1-(4-fluorophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-oldihydrochloride

Example 226

[0843]1-(4-cyanophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-oldihydrochloride

Example 227

[0844]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]l-1(2-naphthylmethyl)piperidin-4-oldihydrochloride

Example 228

[0845]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-[(4-isopropoxyphenyl)methyl]piperidin-4-oldihydrochloride

Example 229

[0846]1-(2-bromophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-oldihydrochloride

Example 230

[0847]1-(3-bromophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-oldihydrochloride

Example 231

[0848]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-(4-nitrophenylmethyl)piperidin-4-oldihydrochloride

Example 232

[0849]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-[3-(trifluoromethyl)phenylmethyl]piperidin-4-oldihydrochloride

Example 233

[0850]1-[4-(methoxycarbonyl)phenylmethyl]-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethylipiperidin-4-oldihydrochloride

Example 234

[0851]1-(2,4-difluorophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-oldihydrochloride

Example 235

[0852]1-[4-fluoro-3-(trifluoromethyl)phenylmethyl]-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-oldihydrochloride

Example 236

[0853]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-(4-trifluoromethoxyphenylmethyl)piperidin-4-oldihydrochloride

Example 237

[0854]1-(2-fluoro-4-isopropoxyphenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-oldihydrochloride

Example 238

[0855]1-(4-biphenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-oldihydrochloride

Example 239

[0856]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-(4-phenoxyphenylmethyl)piperidin-4-oldihydrochloride

Example 240

[0857]1-(4-bromo-2-fluorophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-oldihydrochloride

Example 241

[0858]1-(3-fluorophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-oldihydrochloride

Example 242

[0859]1-(2-fluorophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-oldihydrochloride

Example 243

[0860]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-(3-trifluoromethoxyphenylmethyl)piperidin-4-oldihydrochloride

Example 244

[0861]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-(2-trifluoromethoxyphenylmethyl)piperidin-4-oldihydrochloride

Example 245

[0862]1-(3-chlorophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-oldihydrochloride

Example 246

[0863]1-(2-chlorophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-oldihydrochloride

Example 247

[0864]1-(3-cyanophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-oldihydrochloride

Example 248

[0865]1-(2-cyanophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-oldihydrochloride

Example 249

[0866]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-[2-(trifluoromethyl)phenylmethyl]piperidin-4-oldihydrochloride

Example 250

[0867]1-(2-methoxyphenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-oldihydrochloride

Example 251

[0868]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1(3-nitrophenylmethyl)piperidin-4-oldihydrochloride

Example 252

[0869]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]l-1(2-nitrophenylmethyl)piperidin-4-oldihydrochloride

Example 253

[0870]1-[4-(ethoxycarbonyl)phenylmethyl]-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-oldihydrochloride

Example 254

[0871]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]l-1(2-thienylmethyl)piperidin-4-oldihydrochloride

Example 255

[0872]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]l-1(3-thienylmethyl)piperidin-4-oldihydrochloride

Example 256

[0873]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-[4-(methylthio)phenylmethyl]piperidin-4-oldihydrochloride

Example 257

[0874]1-[2-(methoxycarbonyl)phenylmethyl]-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-oldihydrochloride

Example 258

[0875]1-[3-(methoxycarbonyl)phenylmethyl]-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-oldihydrochloride

Example 259

[0876]1-(3-furylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)-amino]ethyl]piperidin-4-oldihydrochloride

Example 260

[0877]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-[4-(isopropoxycarbonyl)phenylmethyl]piperidin-4-oldihydrochloride

Example 261

[0878]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-[4-(n-propoxycarbonyl)phenylmethyl]piperidin-4-oldihydrochloride

Example 262

[0879]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-(2-phenoxyethyl)piperidin-4-oldihydrochloride

Example 263

[0880]1-[2-(4-fluorophenoxy)ethyl]-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-oldihydrochloride

Example 264

[0881]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-(3-phenylpropyl)piperidin-4-oldihydrochloride

Example 265

[0882]1-(3-biphenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-oldihydrochloride

Example 266

[0883]1-(2-biphenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-oldihydrochloride

Example 267

[0884]1-[2-fluoro-4-(trifluoromethyl)phenylmethyl]-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-oldihydrochloride

Example 268

[0885]4-[2-[N-methyl-N-(4-ethoxyphenyl)amino]ethyl]-1-[4-(trifluoromethyl)phenylmethyl]piperidin-4-oldihydrochloride

Example 269

[0886]1-[4-(methoxycarbonyl)phenylmethyl]-4-[2-[N-methyl-N-(3-isopropoxyphenyl)amino]ethyl]piperidin-4-oldihydrochloride

Example 270

[0887]1-[4-(methoxycarbonyl)phenylmethyl]-4-[2-[N-methyl-N-(2-isopropoxyphenyl)amino]ethyl]piperidin-4-oldihydrochloride

Example 271

[0888]4-[2-[N-(4-isopropoxyphenyl)amino]ethyl]-1-[4-(methoxycarbonyl)phenylmethyl]piperidin-4-oldihydrochloride

Example 272

[0889]4-[2-[N-(4-isopropoxyphenyl)amino]ethyl]-1-[4-(trifluoromethyl)phenylmethyl]piperidin-4-oldihydrochloride

Example 273

[0890]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]-1-hydroxethyl]-1-[4-(trifluoromethyl)phenylmethyl]piperidin-4-oldihydrochloride

Example 274

[0891]4-methoxy-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]-ethyl]-1-[4-(trifluoromethyl)phenylmethyl]piperidinedihydrochloride

Example 275

[0892]4-methoxy-1-[4-(methoxycarbonyl)phenylmethyl]-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidinedihydrochloride

Example 276

[0893]4-[N-methyl-N-(4-isopropoxyphenyl)aminomethyl]-1-[4-(trifluoromethyl)phenylmethyl]piperidin-4-oldihydrochloride

Example 277

[0894]1-[4-(methoxycarbonyl)phenylmethyl]-4-[N-methyl-N-(4-isopropoxyphenyl)aminomethyl]piperidin-4-oldihydrochloride

Example 278

[0895]1-diphenylmethyl-4-[2-[N-methyl-N-(4-isopropoxyphenyl)-amino]ethyl]piperidin-4-oldihydrochloride

Example 279

[0896]1-bis(4-fluorophenyl)methyl-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-oldihydrochloride

Example 280

[0897]1-diphenylmethyl-4-[2-[N-(4-ethoxyphenyl)-N-methylamino]ethyl]piperidin-4-oldihydrochloride

Example 281

[0898]1-diphenylmethyl-4-[2-[N-methyl-N-(3-isopropoxyphenyl)-amino]ethyl]piperidin-4-oldihydrochloride

Example 282

[0899]1-diphenylmethyl-4-[2-[N-methyl-N-(2-isopropoxyphenyl)-amino]ethyl]piperidin-4-oldihydrochloride

Example 283

[0900]1-diphenylmethyl-4-[2-[N-(4-isopropoxyphenyl)-amino]ethyl]piperidin-4-oldihydrochloride

Example 284

[0901]1-diphenylmethyl-4-methoxy-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidinedihydrochloride

Example 285

[0902]1-diphenylmethyl-4-[N-methyl-N-(4-isopropoxyphenyl)-aminomethyl]piperidin-4-oldihydrochloride

Example 286

[0903]1-benzyl-4-[2-[N-(4-n-butoxyphenyl)-N-ethylamino]-ethyl]piperidin-4-oldihydrochloride

Example 287

[0904]1-(4-cyano-2-fluorophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-oldihydrochloride

Example 288

[0905]1-(4-acetylphenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-oldihydrochloride

Example 289

[0906]4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-[4-(trifluoroacetylamino)phenylmethyl]piperidin-4-oldihydrochloride

[0907] Data of physical properties of the compounds in the Examples 1 to143, 146, 162, 176, 177, 183, 196, 198, 201, 207, 210, 233 and 278 arelisted in Table 5.

[0908] The term “Example No. 1-1” denotes the Step 1 in the Example 1.TABLE 5 Example No. I R (cm⁻¹) NMR (ppm) (no mark: 300 MHz, *: 270 MHz)melting point (° C.)  1-1 — CDCl₃: 7.35-7.20(5H, m), 7.04(2H, — d,J=9Hz), 6.91(2H, d, J=9Hz), 5.23(1H, s), 3.84(3H, s), 3.47(2H, s),3.23(3H, s), 2.60-2.48(2H, m), 2.39(2H, ddd, J=12, 12, 3Hz), 2.16(2H,s), 1.71-1.60(2H, m), 1.38(2H, ddd, J=12, 12, 4Hz)  1-2 KBr: 2939,CDCl₃*: 7.35-7.20(5H, m), 6.89(2H, oil 1514, 1246, d, J=9Hz), 6.84(2H,d, J=9Hz), 1038, 814, 3.77(3H, s), 2.52(2H, s), 3.30(2H,  700 t, J=7Hz),2.78(3H, s), 2.66- 2.56(2H, m), 2.38(2H, ddd, J=11, 11, 4Hz),1.72-1.60(6H, m)  2-1 — CDCl₃: 7.35-7.20(5H, m), 7.02(2H, — d, J=9Hz),6.89(2H, d, J=9Hz), 5.24(1H, s), 4.05(2H, q, J=7Hz), 3.47(2H, s),3.23(3H, s), 2.59- 2.49(2H, m), 2.39(2H, ddd, J=12, 12, 2Hz), 2.16(2H,s), 1.71- 1.61(2H, m), 1.46-1.32(2H, m),  2-2 liquid film: CDCl₃:7.38-7.20(5H, m), 6.88(2H, oil 2941, 2814, d, J=9Hz), 6.83(2H, d,J=9Hz), 1520, 1246, 3.98(2H, q, J=7Hz), 3.54(2H, s), 1117, 1051 3.28(2H,t, J=7Hz), 2.77(3H, s), 2.67-2.58(2H, m), 2.46-2.34(2H, m),1.72-1.63(4H, m), 1.68(2H, t, J=7Hz), 1.39(3H, t, J=7Hz)  3-1 — CDCl₃*:7.33-7.19(5H, m), 7.01(2H, — d, J=9Hz), 6.90(2H, d, J=9Hz), 5.24(1H, s),3.98(2H, t, J=7Hz), 3.47(2H, s), 3.23(3H, s), 2.58- 2.48(2H, m),2.39(2H, ddd, J=12, 12, 3Hz), 2.16(2H, s), 1.85- 1.74(2H, m),1.72-1.60(2H, m), 1.38(2H, ddd, J=12, 12, 4Hz), 1.00(3H, t, J=7Hz)  3-2liquid film: CDCl₃: 7.34-7.21(5H, m), 6.88(2H, oil 3398, 2937, d,J=9Hz), 6.83(2H, d, J=9Hz), 1514, 1244, 3.91(2H, t, J=7Hz), 3.52(2H, s), 814, 700 3.28(2H, t, J=7Hz), 2.77(3H, s), 2.66-2.57(2H, m), 2.38(2H,ddd, J=11, 11, 4Hz), 1.78-1.57(8H, m), 1.54-1.41(2H, m), 0.96(3H, t,J=7Hz)  4-1 — CDCl₃: 7.37-7.20(5H, m), 7.01(2H, — d, J=9Hz), 6.88(2H, d,J=9Hz), 5.26(1H, s), 4.62-4.49(1H, m), 3.47(2H, s), 3.23(3H, s), 2.58-2.49(2H, m), 2.39(2H, ddd, J=11, 11, 2Hz), 2.17(2H, s), 1.71- 1.61(2H,m), 1.45-1.31(2H, m), 1.37(6H, d, J=6Hz)  4-2 liquid film: CDCl₃:7.38-7.22(5H, m), 6.86(2H, oil 2976, 2939, d, J=9Hz), 6.82(2H, d,J=9Hz), 2818, 1516, 4.50-4.34(1H, m), 3.54(2H, s), 1242, 1117 3.29(2H,t, J=7Hz), 2.78(3H, s), 2.67-2.59(2H, m), 2.46-2.34(2H, m),1.73-1.62(6H, m), 1.30(6H, d, J=6Hz)  5-1 — CDCl₃*: 7.37-7.19(5H, m),7.00(2H, — d, J=9Hz), 6.90(2H, d, J=9Hz), 5.25(1H, s), 4.30-4.20(1H, m),3.47(2H, s), 3.22(3H, s), 2.58- 2.33(4H, m), 2.17(2H, s), 2.07- 1.95(2H,m), 1.89-1.76(2H, m), 1.71-1.28(10H, m)  5-2 KBr: 2935, CDCl₃*:7.34-7.20(5H, m), 6.89- 68.1- 2856, 1512, 6.79(4H, m), 4.16-4.02(1H, m),70.1 1248, 1051, 3.76(1H, s), 3.52(2H, s), 3.29(2H,  831 t, J=7Hz),2.77(3H, s), 2.66- 2.55(2H, m), 2.45-2.32(2H, m), 2.03-1.93(2H, m),1.86-1.20(14H, m)  6-1 — CDCl₃*: 7.46-6.97(14H, m), 5.19(1H, — s),3.48(2H, s), 3.25(3H, s), 2.61- 2.35(4H, m), 2.19(2H, s), 1.72- 1.60(2H,m), 1.48-1.35(2H, m)  6-2 liquid film: CDCl₃*: 7.34-7.22(7H, m),7.02(1H, oil 2939, 2812, dddd, J=7, 7, 1, 1Hz), 6.98- 1589, 1512,6.92(4H, m), 6.82(2H, d, J=9Hz), 1489, 1238 3.52(2H, s), 3.40(2H, t,J=7Hz), 2.86(3H, s), 2.71(1H, br. s), 2.69- 2.58(2H, m), 2.43-2.30(2H,m), 1.77-1.59(6H, m)  7-1 — CDCl₃: 7.33-7.19(6H, m), 6.92- — 6.85(1H,m), 6.72-6.63(2H, m), 5.21(1H, s), 3.95(2H, t, J=7Hz), 3.47(2H, s),3.25(3H, s), 2.59- 2.49(2H, m), 2.39(2H, ddd, J=12, 12, 2Hz), 2.20(2H,s), 1.84- 1.61(4H, m), 1.58-1.40(2H, m), 1.39(2H, ddd, J=12, 12, 4Hz),0.99(3H, t, J=7Hz)  7-2 liquid film: CDCl₃: 7.38-7.20(5H, m), 7.12(1H,oil 2935, 2869, dd, J=8, 8Hz), 6.42-6.36(1H, m), 2809, 1610,6.34-6.28(2H, m), 3.94(2H, t, 1500, 1172 J=7Hz), 3.52(2H, s), 3.44(2H,t, J=8Hz), 2.87(3H, s), 2.69-2.59(2H, m), 2.42-2.30(2H, m), 1.80-1.40(10H, m), 0.97(3H, t, J=7Hz)  8-1 — CDCl₃: 7.40-7.18(6H, m), 7.12- —7.05(1H, m), 6.99-6.90(2H, m), 5.35(1H, s), 4.04-3.90(2H, m), 3.46(2H,s), 3.17(3H, s), 2.58- 2.33(4H, m), 2.14(1H, d, J=16Hz), 2.06(1H, d,J=16Hz), 1.81-1.59(4H, m), 1.53-1.29(4H, m), 0.93(3H, t, J=7Hz)  8-2liquid film: CDCl₃*: 7.35-7.18(5H, m), 7.08- oil 2937, 2872, 7.00(2H,m), 6.92-6.83(2H, m), 2812, 1500, 5.03(1H, s), 3.99(2H, t, J=7Hz), 1454,1238, 3.51(2H, s), 3.20(2H, t, J=6Hz),  744 2.69(3H, s), 2.60-2.48(2H,m), 2.41(2H, ddd, J=11, 11, 3Hz), 1.89- 1.75(2H, m), 1.72-1.42(8H, m),0.98(3H, t, J=7Hz)  9-1 — CDCl₃: 7.35-7.19(5H, m), 6.95(1H, — dd, J=9,9Hz), 6.92-6.81(2H, m), 5.10(1H, s), 4.06(2H, t, J=6Hz), 3.48(2H, s),3.22(3H, s), 2.59- 2.49(2H, m), 2.39(2H, ddd, J=12, 12, 2Hz), 2.17(2H,s), 1.89- 1.78(2H, s), 1.71-1.47(4H, m), 1.39(2H, ddd, J=12, 12, 4Hz),1.00(3H, t, J=7Hz)  9-2 liquid film: CDCl₃: 7.35-7.25(5H, m), 6.87(1H,oil 2954, 2871, dd, J=9, 9Hz), 6.60(1H, dd, J=14, 1520, 1248, 3Hz),6.49(1H, ddd, J=9, 3, 1Hz), 1217 3.96(2H, t, J=7Hz), 3.52(2H, s),3.35(2H, t, J=7Hz), 2.81(3H, s), 2.68-2.55(3H, m), 2.42-2.30(2H, m),1.80-1.60(8H, m), 1.55-1.42(2H, m), 0.96(3H, t, J=7Hz)  10-1 — CDCl₃:7.36-7.21(5H, m), 7.21(2H, — d, J=8Hz), 7.02(2H, d, J=8Hz), 5.27(1H, s),3.47(2H, s), 3.25(3H, s), 2.61(2H, t, J=8Hz), 2.58- 2.48(2H, m),2.39(2H, ddd, J=12, 12, 3Hz), 2.17(2H, s), 1.73- 1.50(4H, m), 1.38(2H,ddd, J=12, 12, 4Hz), 0.97(3H, t, J=7Hz)  10-2 liquid film: CDCl₃:7.36-7.23(5H, m), 7.06(2H, oil 2929, 2870, d, J=9Hz), 0.78(2H, d,J=9Hz), 2811, 1616, 3.53(2H, s), 3.39(2H, t, J=7Hz), 1522, 1365 2.84(3H,s), 2.67-2.57(2H, m), 2.49(2H, t, J=8Hz), 2.45-2.33(2H, m),1.76-1.53(8H, m), 0.93(3H, t, J=7Hz)  11-1 — CDCl₃*: 7.35-7.20(5H, m),7.08(2H, — d, J=9Hz), 6.91(2H, d, J=9Hz), 4.25(1H, s), 3.98(2H, t,J=6Hz), 3.54(1H, s), 3.49(2H, s), 3.32(3H, s), 3.29(3H, s),2.70-2.55(2H, m), 2.48-2.25(2H, m), 1.90-1.71(3H, m), 1.65-1.22(5H, m),1.01(3H, t, J=7Hz)  11-2 liquid film: CDCl₃*: 7.36-7.21(5H, m), 6.82(2H,oil 2933, 1514, d, J=9Hz), 6.73(2H, d, J=9Hz), 1365, 1242, 3.90(2H, t,J=6Hz), 3.55-3.46(1H, 1101, 1076, m), 3.53(2H, s), 3.38(3H, s),  8143.27(1H, dd, J=14, 8Hz), 3.19(1H, dd, J=8, 3Hz), 2.92(3H, s), 2.76-2.65(3H, m), 2.41-2.29(2H, m), 1.80-1.40(8H, m), 0.97(3H, t, J=7Hz) 12-1 — CDCl₃: 7.33-7.20(5H, m), 7.10(2H, — d, J=9Hz), 6.90(2H, d,J=9Hz), 4.04(1H, s), 3.98(2H, t, J=6Hz), 3.96(1H, s), 3.49(1H, d,J=13Hz), 3.46(1H, d, J=13Hz), 3.24(3H, s), 2.70-2.59(2H, m),2.42-2.21(2H, m), 1.85-1.75(3H, m), 1.59-1.19(5H, m), 1.01(3H, t,J=7Hz), 0.88(9H, s), 0.07(3H, s), −0.05(3H, s)  12-2 KBr: 3460, CDCl₃*:7.38-7.22(5H, m), 6.86(2H, 79.2- 2949, 1518, d, J=9Hz), 6.83(2H, d,J=9Hz), 80.4 1244, 1045, 3.91(2H, t, J=6Hz), 3.64-3.55(1H,  810 m),3.57(2H, s), 3.29(1H, dd, J=13, 11Hz), 3.08(1H, dd, J=13, 3Hz),2.82-2.68(2H, m), 2.79(3H, s), 2.50-2.32(2H, m), 1.00-1.40(8H, m),0.97(3H, t, J=7Hz)  13-1 — CDCl₃: 7.71(1H, s), 7.38-7.20(5H, — m),7.36(2H, d, J=9Hz), 6.84(2H, d, J=9Hz), 3.95(1H, s), 3.92(2H, t, J=7Hz),3.52(2H, s), 2.65-2.56(2H, m), 2.47(2H, s), 2.43(2H, ddd, J=12, 12,3Hz), 1.80-1.62(6H, m), 1.54-1.41(2H, m), 0.96(3H, t, J=7Hz)  13-2 KBr:3263, CDCl₃*: 7.35-7.20(5H, m), 6.78(2H, 119.8-  2937, 1512, d, J=9Hz),6.63(2H, d, J=9Hz), 120.2 1242, 1074, 3.89(2H, t, J=6Hz), 3.52(2H, s), 731 3.27(2H, t, J=6Hz), 2.68-2.57(2H, m), 2.43-2.31(2H, m), 1.80-1.40(10H, m), 0.96(3H, t, J=7Hz)  14-1 — DMSO-d₆*: 8.53(1H, s), 7.35- —7.20(5H, m), 6.60(2H, d, J=9Hz), 6.56(2H, d, J=9Hz), 4.13(1H, s),3.42(2H, s), 3.30-3.20(2H, m), 2.69(3H, s), 2.46-2.20(4H, m),1.52-1.40(6H, m)  14-2 liquid film: CDCl₃*: 7.36-7.18(5H, m), 6.88(2H,oil 2937, 1512, d, J=10Hz), 6.83(2H, d, J=10Hz), 1473, 1454, 3.87(2H, t,J=7Hz), 3.52(2H, s), 1242, 822, 3.28(2H, t, J=7Hz), 2.77(3H, s),  7002.67-2.57(2H, m), 2.36(2H, ddd, J=11, 11, 4Hz), 1.85-1.52(8H, m),1.02(3H, t, J=7Hz) 15 KBr: 2939, CDCl₃*: 7.36-7.20(5H, m), 6.88(2H,58.5- 1512, 1242, d, J=9Hz), 6.83(2H, d, J=9Hz), 60.3 1030, 824 3.90(2H,t, J=7Hz), 3.52(2H, s), 3.28(2H, t, J=7Hz), 2.77(3H, s), 2.67-2.57(2H,m), 2.36(2H, ddd, J=11, 11, 4Hz), 1.81-1.30(12H, m), 0.92(3H, t, J=7Hz)16 KBr: 2937, CDCl₃*: 7.35-7.20(5H, m), 6.88(2H, 50.6- 1516, 1470, d,J=9Hz), 6.83(2H, d, J=9Hz), 52.5 1248, 1036, 3.91(1H, s), 3.67(2H, d,J=7Hz),  814 3.52(2H, s), 3.28(2H, t, J=7Hz), 2.77(3H, s), 2.67-2.57(2H,m), 2.38(2H, ddd, J=11, 11, 4Hz), 2.13- 1.98(1H, m), 1.73-1.52(6H, m),1.01(6H, d, J=7Hz) 17 KBr: 3369, CDCl₃*: 7.35-7.20(5H, m), 6.85(2H,68.6- 2931, 1512, d, J=9Hz), 6.75(2H, d, J=9Hz), 69.8 1248, 8184.62-4.50(1H, m), 3.52(2H, s), 3.28(2H, t, J=7Hz), 2.77(3H, s),2.66-2.55(2H, m), 2.48-2.30(4H, m), 2.23-2.03(2H, m), 1.90-1.55(8H, m)18 liquid film: CDCl₃*: 7.36-7.20(5H, m), 6.87(2H, oil 2939, 1512, d,J=9Hz), 6.83(2H, d, J=9Hz), 1238, 1028, 3.78(1H, s), 3.74(2H, d, J=7Hz), 812, 700 3.52(2H, s), 3.29(2H, t, J=7Hz), 2.77(3H, s), 2.68-2.56(2H,m), 2.38(2H, ddd, J=11, 11, 5Hz), 1.74- 1.56(6H, m), 1.33-1.18(1H, m),0.67-0.58(2H, m), 0.36-0.29(2H, m)  19-1 — CDCl₃: 6.90(2H, d, J=9Hz),6.84(2H, — d, J=9Hz), 3.91(2H, t, J=7Hz), 3.29(2H, t, J=7Hz), 3.00(2H,ddd, J=12, 12, 3Hz), 2.83(2H, ddd, J=12, 4, 4Hz), 2.78(3H, s), 1.79-1.42(10H, m), 0.97(3H, t, J=7Hz)  19-2 KBr: 1512, CDCl₃: 6.92-6.72(7H,m), 5.94(2H, 72.4- 1487, 1244, s), 3.91(2H, t, J=7Hz), 3.46(2H, 74.21041, 822 s), 3.28(2H, t, J=7Hz), 2.77(3H, s), 2.68-2.57(2H, m),2.46-2.32(2H, m), 1.80-1.58(8H, m), 1.55-1.40(2H, m), 0.96(3H, t, J=7Hz)20 KBr: 2951, CDCl₃: 7.26(4H, s), 6.89(2H, d, 67.7- 2926, 1512, J=9Hz),6.83(2H, d, J=9Hz), 68.3 1242, 825 4.00(1H, s), 3.91(2H, t, J=7Hz),3.48(2H, s), 3.28(2H, t, J=7Hz), 2.77(3H, s), 2.63-2.53(2H, m), 2.37(2H,ddd, J=11, 11, 3Hz), 1.80- 1.40(10H, m), 0.96(3H, t, J=7Hz) 21 KBr:2951, CDCl₃: 7.56(2H, d, J=8Hz), 7.45(2H, 77.4- 2933, 1516, d, J=8Hz),6.90(2H, d, J=9Hz), 78.2 1331, 1242, 6.83(2H, d, J=9Hz), 3.91(2H, t,1161, 1122, J=7Hz), 3.57(2H, s), 3.28(2H, t, 1066 J=7Hz), 2.77(3H, s),2.63-2.54(2H, m), 2.41(2H, ddd, J=11, 11, 3Hz), 1.79-1.42(10H, m),0.96(3H, t, J=7Hz) 22 KBr: 2937, CDCl₃*: 7.60(2H, d, J=8Hz), 83.5- 2227,1516, 7.45(2H, d, J=8Hz), 6.90(2H, d, 85.5 1242, 824 J=9Hz), 6.84(2H, d,J=9Hz), 3.91(2H, t, J=7Hz), 3.56(2H, s), 3.28(2H, t, J=7Hz), 2.77(3H,s), 2.62-2.50(2H, m), 2.42(2H, ddd, J=11, 11, 3Hz), 1.80-1.40(10H, m),0.97(3H, t, J=7Hz) 23 KBr: 3527, CDCl₃: 7.98(2H, d, J=8Hz), 7.41(2H,82.5- 2937, 1716, d, J=8Hz), 6.89(2H, d, J=9Hz), 82.8 1518, 1282,6.83(2H, d, J=9Hz), 3.91(2H, t, 1232 J=6Hz), 3.91(3H, s), 3.57(2H, s),3.28(2H, t, J=7Hz), 2.77(3H, s), 2.66-2.53(2H, m), 2.48-2.34(2H, m),1.80-1.40(10H, m), 0.96(3H, t, J=7Hz) 24 KBr: 2951, CDCl₃: 7.17(2H, d,J=9Hz), 6.87(2H, 71.3- 2927, 1612, d, J=9Hz), 6.83(2H, d, J=9Hz), 73.01512, 1240, 6.70(2H, d, J=9Hz), 3.91(2H, t,  814 J=7Hz), 3.84(1H, s),3.43(2H, s), 3.28(2H, t, J=7Hz), 2.93(6H, s), 2.77(3H, s), 2.66-2.55(2H,m), 2.34(2H, ddd, J=11, 11, 4Hz), 1.80- 1.40(10H, m), 0.96(3H, t, J=7Hz)25 KBr: 2931, CDCl₃*: 7.09(2H, d, J=9Hz), oil 2870, 1614, 6.89(2H, d,J=9Hz), 6.83(2H, d, 1514, 1471, J=9Hz), 6.63(2H, d, J=9Hz), 12443.91(2H, t, J=7Hz), 3.48(2H, s), 3.27(2H, t, J=6Hz), 2.76(3H, s),2.72-2.63(2H, m), 2.48-2.35(2H, m), 1.80-1.40(10H, m), 0.96(3H, t,J=7Hz) 26 liquid film: CDCl₃*: 7.24(2H, d, J=9Hz), 6.92- oil 2935, 1612,6.80(6H, m), 3.91(2H, t, J=6Hz), 1514, 1468, 3.80(3H, s), 3.48(2H, s),3.28(2H, 1244, 1036 t, J=7Hz) 2.77(3H, s), 2.70- 2.55(2H, m),2.46-2.30(2H, m), 1.80-1.40(10H, m), 0.96(3H, t, J=7Hz) 27 KBr: 2937,CDCl₃*: 7.22(1H, dd, J=8, 8Hz), oil 1512, 1468, 6.96-6.75(7H, m),3.91(2H, t, 1244, 1047 J=7Hz), 3.81(3H, s), 3.50(2H, s), 3.29(2H, t,J=7Hz), 2.77(3H, s), 2.67-2.56(2H, m), 2.38(2H, ddd, J=11, 11, 4Hz),1.80-1.40(10H, m), 0.96(3H, t, J=7Hz) 28 KBr: 2937, CDCl₃*: 7.35(1H, dd,J=7, 2Hz), oil 1512, 1464, 7.22(1H, ddd, J=8, 8, 2Hz), 6.96- 1242, 7566.78(6H, m), 3.91(2H, t, J=7Hz), 3.81(3H, s), 3.77(1H, s), 3.58(2H, s),3.29(2H, t, J=7Hz), 2.78(3H, s), 2.71-2.60(2H, m), 2.53-2.38(2H, m),1.80-1.40(10H, m), 0.96(3H, t, J=7Hz) 29 KBr: 2943, CDCl₃: 7.30-7.21(1H,m), 7.10- 46.7- 2922, 1512, 7.04(2H, m), 6.97-6.88(1H, m), 47.2 1242,825 6.89(2H, d, J=9Hz), 6.83(2H, d, J=9Hz), 3.91(2H, t, J=7Hz), 3.51(2H,s), 3.28(2H, t, J=7Hz), 2.77(3H, s), 2.64-2.55(2H, m), 2.39(2H, ddd,J=11, 11, 4Hz), 1.79- 1.57(8H, m), 1.54-1.41(2H, m), 0.96(3H, t, J=7Hz)30 KBr: 2947, CDCl₃: 7.17(1H, ddd, J=12, 8, 2Hz), 49.8- 2922, 1512,7.13-6.97(2H, m), 6.90(2H, d, 50.5 1284, 1242, J=9Hz), 6.83(2H, d,J=9Hz),  825 3.91(2H, t, J=7Hz), 3.46(2H, s), 3.28(2H, t, J=7Hz),2.77(3H, s), 2.62-2.53(2H, m), 2.38(2H, ddd, J=11, 11, 3Hz),1.79-1.41(10H, m), 0.96(3H, t, J=7Hz) 31 KBr: 2920, CDCl₃*: 7.23(2H, d,J=8Hz), 73.3- 2872, 1514, 7.13(2H, d, J=8Hz), 6.88(2H, d, 75.0 1475,1242, J=9Hz), 6.83(2H, d, J=9Hz),  824 3.91(2H, t, J=6Hz), 3.54(2H, s),3.27(2H, t, J=7Hz), 2.76(3H, s), 2.74-2.60(2H, m), 2.50-2.35(2H, m),2.33(3H, s), 1.80-1.62(8H, m), 1.55-1.40(2H, m), 0.96(3H, t, J=7Hz) 32KBr: 2937, CDCl₃*: 7.22-7.08(4H, m), 6.90(2H, 94.4- 1512, 1244, d,J=9Hz), 6.84(2H, d, J=9Hz), 94.6 1124, 743 4.06(1H, s), 3.92(2H, t,J=6Hz), 3.33-3.04(5H, m), 2.91(2H, dd, J=15, 9Hz), 2.80-2.70(2H, m),2.78(3H, s), 2.47(2H, ddd, J=11, 11, 3Hz), 1.80-1.60(8H, m), 1.55-1.41(2H, m), 0.97(3H, t, J=7Hz)  33-1 — CDCl₃*: 7.21(2H, dd, J=9, 5Hz),— 7.00(2H, dd, J=9, 9Hz), 6.93(2H, d, J=9Hz), 6.84(2H, d, J=9Hz), 4.42-4.33(1H, m), 3.92(2H, t, J=6Hz), 3.70(2H, s), 3.67-3.57(1H, m), 3.42(1H,ddd, J=13, 13, 3Hz), 3.22(2H, t, J=6Hz), 3.08(1H, ddd, J=13, 13, 3Hz),2.74(3H, s), 1.80- 1.36(9H, m), 1.19(1H, ddd, J=13, 13, 5Hz), 0.97(3H,t, J=7Hz)  33-2 KBr: 2929, CDCl₃*: 7.16(2H, dd, J=9, 6Hz), 75.5- 1512,1471, 6.96(2H, dd, J=9, 9Hz), 6.92(2H, d, 75.8 1242, 1217, J=9Hz),6.84(2H, d, J=9Hz),  814 3.92(2H, t, J=7Hz), 3.29(2H, t, J=7Hz),2.84-2.68(4H, m), 2.78(3H, s), 2.64-2.55(2H, m), 2.45(2H, ddd, J=11, 11,3Hz), 1.80-1.60(8H, m), 1.55-1.42(2H, m), 0.97(3H, t, J=7Hz) 34 KBr:2935, CDCl₃: 7.29(2H, dd, J=9, 6Hz), oil 2870, 2814, 6.99(2H, dd, J=9,9Hz), 6.89(2H, d, 1512, 1242, J=9Hz), 6.83(2H, d, J=9Hz), 1221 3.91(2H,t, J=7Hz), 3.50(2H, s), 3.28(2H, t, J=7Hz), 2.77(3H, s), 2.66-2.56(2H,m), 2.46-2.34(2H, m), 1.80-1.62(8H, m), 1.57-1.41(2H, m), 0.96(3H, t,J=7Hz) 35 KBr: 2956, CDCl₃*: 7.33-7.18(5H, m), 6.85(2H, oil 2933, 1512,d, J=9Hz), 6.82(2H, d, J=9Hz), 1242, 702 3.90(2H, t, J=6Hz), 3.42(1H, q,J=7Hz), 3.27(2H, t, J=7Hz), 2.80- 2.71(1H, m), 2.76(3H, s), 2.56-2.46(1H, m), 2.42-2.26(2H, m), 1.79-1.40(10H, m), 1.38(3H, d, J=7Hz),0.96(3H, t, J=7Hz) 36 liquid film: CDCl₃*: 8.02-7.98(2H, m), 7.60- oil2935, 1695, 7.40(3H, m) 6.91(2H, d, J=9Hz), 1514, 1242, 6.84(2H, d,J=9Hz), 3.91(2H, t, 1221 J=6Hz), 3.85(2H, s), 3.29(2H, t, J=6Hz),2.83-2.73(2H, m), 2.78(3H, s), 2.53(2H, ddd, J=11, 11, 4Hz),1.82-1.64(8H, m), 1.55-1.41(2H, m), 0.97(3H, t, J=7Hz) 37 liquid film:CDCl₃*: 8.05(2H, dd, J=9, 5Hz), oil 2958, 2935, 7.12(2H, dd, J=9, 9Hz),6.92(2H, d, 1599, 1514, J=9Hz), 6.84(2H, d, J=9Hz), 1240 3.91(2H, t,J=6Hz), 3.84(2H, s), 3.28(2H, t, J=6Hz), 2.86-2.72(2H, m), 2.77(3H, s),2.58(2H, ddd, J=11, 11, 5Hz), 1.83-1.65(8H, m), 1.55-1.40(2H, m),0.97(3H, t, J=7Hz)  38-1 — CDCl₃*: 6.83(2H, d, J=9Hz), — 6.76(2H, d,J=9Hz), 3.91(2H, t, J=7Hz), 3.50(1H, dd, J=14, 3Hz), 3.40(3H, s),3.27(1H, dd, J=14, 8Hz), 3.18(1H, dd, J=8, 3Hz), 3.06- 2.83(4H, m),2.92(3H, s), 1.80- 1.40(8H, m), 0.97(3H, t, J=7Hz)  38-2 KBr: 2933,CDCl₃: 7.32-7.16(5H, m), 6.83(2H, 70.8- 2821, 1514, d, J=9Hz), 6.75(2H,d, J=9Hz), 71.9 1244, 1103, 3.91(2H, t, J=7Hz), 3.52(1H, dd,  808 J=14,3Hz), 3.40(3H, s), 3.28(1H, dd, J=14, 8Hz), 3.21(1H, dd, J=8, 3Hz),2.93(3H, s), 2.88-2.78(4H, m), 2.68-2.60(2H, m), 2.48-2.37(2H, m),1.85-1.58(6H, m), 1.55-1.42(2H, m), 0.97(3H, t, J=7Hz)  39-1 — CDCl₃*:7.04(2H, d, J=9Hz), — 6.91(2H, d, J=9Hz), 5.30(1H, s), 3.98(2H, t,J=6Hz), 3.24(3H, s), 2.99(2H, ddd, J=12, 12, 3Hz), 2.69(2H, ddd, J=12,4, 4Hz), 2.18(2H, s), 1.87-1.43(6H, m), 1.37-1.25(2H, m), 1.00(3H, t,J=7Hz  39-2 — CDCl₃: 7.13(2H, d, J=9Hz), 6.98(2H, — d, J=9Hz), 6.92(2H,d, J=9Hz), 6.82(2H, d, J=9Hz), 4.37-4.28(1H, m), 3.99(2H, t, J=6Hz),3.79(3H, s), 3.63(2H, s), 3.61-3.52(1H, m), 3.46-3.34(1H, m), 3.22(3H,s), 3.03(1H, ddd, J=13, 13, 3Hz), 2.09(1H, d, J=16Hz), 2.08(1H, d,J=16Hz), 1.86-1.45(6H, m), 1.19(1H, ddd, J=13, 13, 5Hz), 1.00(3H, t,J=7Hz), 0.94(1H, ddd, J=13, 13, 5Hz)  39-3 KBr: 2935, CDCl₃*: 7.12(2H,d, J=9Hz), 61.1- 1512, 1464, 6.90(2H, d, J=9Hz), 6.84(2H, d, 61.4 1246,1103, J=9Hz), 6.83(2H, d, J=9Hz), 1028, 827 3.92(2H, t, J=6Hz), 3.78(3H,s), 3.29(2H, t, J=7Hz), 2.82-2.66(4H, m), 2.78(3H, s), 2.64-2.54(2H, m),2.52-2.38(2H, m), 1.80-1.60(8H, m), 1.56-1.40(2H, m), 0.97(3H, t, J=7Hz 40-1 — CDCl₃*: 7.28-7.17(1H, m), 7.01(2H, — d, J=9Hz), 6.93(2H, d,J=9Hz), 6.86-6.75(2H, m), 5.43(1H, s), 4.38-4.27(1H, m), 3.99(2H, t,J=6Hz), 3.71-3.41(4H, m), 3.23(3H, s), 3.12-3.00(1H, m), 2.13(2H, s),1.86-1.44(6H, m), 1.29-1.05(2H, m), 1.00(3H, t, J=7Hz)  40-2 liquidfilm: CDCl₃*: 7.22-7.10(1H, m), 6.95- oil 2939, 1510, 6.72(6H, m),3.92(2H, t, J=6Hz), 1244, 1136, 3.29(2H, t, J=6Hz), 2.86-2.65(4H,  964m), 2.78(3H, s), 2.65-2.40(4H, m), 1.80-1.41(10H, m), 0.97(3H, t, J=7Hz) 41-1 — CDCl₃*: 7.00(2H, d, J=9Hz), — 6.92(2H, d, J=9Hz), 6.73(1H, d,J=2Hz), 6.72(1H, d, J=8Hz), 6.64(1H, dd, J=8, 2Hz), 5.94- 5.91(2H, m),5.39(1H, s), 4.38- 4.28(1H, m), 3.98(2H, t, J=6Hz), 3.61-3.35(2H, m),3.59(2H, s), 3.23(3H, s), 3.04(1H, ddd, J=13, 13, 3), 2.10(2H, s),1.86-1.73(2H, m), 1.71-1.44(4H, m), 1.21(1H, ddd, J=13, 13, 5Hz),1.07-0.93(1H, m), 1.00(3H, t, J=7Hz)  41-2 KBr: 3361, CDCl₃: 6.90(2H, d,J=9Hz), 6.84(2H, 55.1- 2935, 1514, d, J=9Hz), 6.75-6.62(3H, m), 55.51246, 1039, 5.91(2H, s), 3.91(2H, t, J=7Hz),  814 3.29(2H, t, J=7Hz),2.79-2.67(4H, m, 2.78(3H, s), 2.62-2.53(2H, m), 2.44(2H, ddd, J=11, 11,3), 1.80- 1.59(8H, m), 1.55-1.41(2H, m), 0.97(3H, t, J=7Hz)  42-1 —CDCl₃*: 7.33-7.07(5H, m), 7.02(2H, — d, J=9Hz), 6.94(2H, d, J=9Hz),5.41(1H, s), 4.40-4.29(1H, m), 3.99(2H, t, J=6Hz), 3.53-3.30(2H, m),3.24(3H, s), 3.07-2.89(3H, m), 2.62-2.53(2H, m), 2.10(2H, s),1.86-1.72(2H, m), 1.710-1.43(4H, m), 1.18(1H, ddd, J=13, 13, 5Hz),0.99(3H, t, J=7Hz), 0.94(1H, ddd, J=13, 13, 5Hz)  42-2 liquid film:CDCl₃*: 7.32-7.13(5H, m), 6.89(2H, oil 2937, 2870, d, J=9Hz), 6.83(2H,d, J=9Hz), 1514, 1471, 3.91(2H, t, J=6Hz), 3.28(2H, t, 1242 J=7Hz),2.77(3H, s), 2.68-2.57(4H, m), 2.45-2.28(4H, m), 1.91- 1.40(12H, m),0.97(3H, t, J=7Hz)  43-1 — CDCl₃*: 7.31-7.23(2H, m), 7.04- — 6.85(7H,m), 4.66(1H, d, J=13Hz), 4.63(1H, d, J=13Hz), 4.36-4.24(1H, m), 3.98(2H,t, J=6Hz), 3.75- 3.64(1H, m), 3.56-3.43(1H, m), 3.24(3H, s),3.15-3.02(1H, m), 2.13(2H, s), 1.86-1.44(6H, m), 1.32-1.16(2H, m),1.00(3H, t, J=7Hz)  43-2 liquid film: CDCl₃*: 7.32-7.25(2H, m), 6.98-oil 2935, 1514, 6.80(7H, m), 4.12(2H, t, J=6Hz), 1471, 1244, 3.91(2H, t,J=6Hz), 3.29(2H, t, 1038, 754 J=6Hz), 2.84(2H, t, J=6Hz), 2.80- 2.68(2H,m), 2.78(3H, s), 2.54(2H, ddd, J=11, 11, 4Hz), 1.80-1.58(8H, m),1.56-1.40(2H, m), 0.97(3H, t, J=7Hz)  44-1 — CDCl₃*: 7.33-7.17(5H, m),6.98(2H, — d, J=9Hz), 6.92(2H, d, J=9Hz), 5.38(1H, s), 4.38-4.28(1H, m),3.99(2H, t, J=6Hz), 3.69(2H, s), 3.61-3.51(1H, m), 3.46-3.34(1H, m),3.22(3H, s), 3.04(1H, ddd, J=13, 13, 3Hz), 2.08(2H, s), 1.86- 1.73(2H,m), 1.71-1.43(4H, m), 1.30-1.14(1H, m), 1.00(3H, t, J=7Hz),0.97-0.85(1H, m)  44-2 liquid film: CDCl₃: 7.33-7.16(5H, m), 6.91(2H,oil 2953, 2937, d, J=9Hz), 6.84(2H, d, J=9Hz), 2870, 1514, 3.92(2H, t,J=6Hz), 3.30(2H, t, 1244 J=6Hz), 2.87-2.71(4H, m), 2.78(3H, s),2.68-2.60(2H, m), 2.52-2.42(2H, m), 1.80-1.62(8H, m), 1.55-1.41(2H, m),0.97(3H, t, J=7Hz)  45-1 — CDCl₃*: 7.71(1H, s), 7.37(2H, d, — J=9Hz),6.85(2H, d, J=9Hz), 3.94(2H, t, J=7Hz), 3.03(2H, ddd, J=13, 10, 3Hz),2.84(2H, ddd, J=13, 4, 4Hz), 2.49(2H, s), 1.81-1.40(8H, m), 0.97(3H, t,J=7Hz)  45-2 — CDCl₃: 7.46(1H, s), 7.35(2H, d, — J=9Hz), 7.21(2H, dd,J=9, 5Hz), 7.00(2H, dd, J=9, 9Hz), 6.85(2H, d, J=9Hz), 4.65(1H, s),4.45-4.35(1H, m), 3.94(2H, t, J=6Hz), 3.70(2H, s), 3.70-3.60(1H, m),3.55-3.42(1H, m), 3.11(1H, ddd, J=13, 13, 3Hz), 2.39(2H, s),1.82-1.65(4H, m), 1.55-1.35(3H, m), 1.30-1.14(1H, m), 0.97(3H, t, J=7Hz) 45-3 KBr: 3269, CDCl₃: 7.16(2H, dd, J=9, 5Hz), 92.8- 2935, 1512,6.96(2H, dd, J=9, 9Hz), 6.79(2H, d, 94.6 1236, 825 J=9Hz), 6.65(2H, d,J=9Hz), 3.89(2H, t, J=7Hz), 3.29(2H, t, J=6Hz), 2.83-2.67(4H, m), 2.63-2.54(2H, m), 2.42(2H, ddd, J=12, 12, 4Hz), 1.80(2H, t, J=6Hz), 1.76-1.67(6H, m), 1.55-1.40(2H, m), 0.96(3H, t, J=7Hz)  46-1 — CDCl₃:7.34-7.20(5H, m), 7.00(2H, — d, J=9Hz), 6.81(2H, d, J=9Hz), 5.26(1H, s),4.69-4.58(1H, m), 3.47(2H, s), 3.22(3H, s), 2.59- 2.34(6H, m),2.28-2.12(2H, m), 2.16(2H, s), 1.97-1.61(4H, m), 1.39(2H, ddd, J=12, 12,4Hz)  46-2 — CDCl₃*: 7.02(2H, d, J=9Hz), — 6.82(2H, d, J=9Hz), 5.30(1H,s), 4.70-4.57(1H, m), 3.23(3H, s), 2.99(2H, ddd, J=12, 12, 3Hz),2.70(2H, ddd, J=12, 4, 4Hz), 2.53- 2.42(2H, m), 2.28-2.11(2H, m),2.17(2H, s), 1.97-1.55(4H, m), 1.36-1.26(2H, m)  46-3 — CDCl₃:7.34-7.18(5H, m), 6.96(2H, — d, J=9Hz), 6.83(2H, d, J=9Hz), 5.38(1H, s),4.71-4.59(1H, m), 4.40-4.30(1H, m), 3.70(2H, s), 3.60-3.51(1H, m),3.40(1H, ddd, J=13, 13, 2Hz), 3.21(3H, m), 3.04(1H, ddd, J=13, 13, 3Hz),2.55- 2.42(2H, m), 2.28-2.12(2H, m), 2.09(1H, d, J=16Hz), 2.07(1H, d,J=16Hz), 1.97-1.51(4H, m), 1.20(1H, ddd, J=13, 13, 5Hz), 0.93(1H, ddd,J=13, 13, 5Hz)  46-4 liquid film: CDCl₃*: 7.35-7.20(5H, m), 6.89(2H, oil1514, 1469, d, J=9Hz), 6.75(2H, d, J=9Hz), 1454, 1354, 4.65-4.50(1H, m),3.98(1H, s), 1246 3.30(2H, t, J=8Hz), 2.84-2.57(6H, m), 2.78(3H, s),2.53-2.37(4H, m), 2.22-2.06(2H, m), 1.90-1.60(8H, m)  47-1 — CDCl₃*:7.18(2H, dd, J=9, 5Hz), — 7.02-6.93(4H, m), 6.83(2H, d, J=9Hz), 5.40(1H,s), 4.71-4.58(1H, m), 4.38-4.28(1H, m), 3.66(2H, s), 3.60-3.50(1H, m),3.42(1H, ddd, J=13, 13, 3Hz), 3.21(3H, s), 3.03(1H, ddd, J=13, 13, 3Hz),2.56- 2.42(2H, m), 2.30-2.01(4H, m), 1.98-1.83(1H, m), 1.82-1.53(3H, m),1.19(1H, ddd, J=13, 13, 5Hz), 0.93(1H, ddd, J=13, 13, 5Hz)  47-2 liquidfilm: CDCl₃: 7.16(2H, dd, J=8, 6Hz), oil 2941, 2814, 7.01-6.92(2H, m),6.89(2H, d, 1510, 1354, J=9Hz), 6.76(2H, d, J=9Hz), 4.63- 1244, 1132,4.51(1H, m), 3.29(2H, t, J=6Hz), 1086, 825 2.84-2.69(4H, m), 2.78(3H,s), 2.64-2.56(2H, m), 2.52-2.36(4H, m), 2.23-2.07(2H, m), 1.90-1.57(8H,m)  48-1 — CDCl₃: 7.41-7.15(4H, m), 6.99(2H, — d, J=9Hz), 6.84(2H, d,J=9Hz), 5.42(1H, s), 4.71-4.59(1H, m), 4.41-4.31(1H, m), 3.79(1H, d,J=16Hz), 3.76(1H, d, J=16Hz), 3.59- 3.39(2H, m), 3.23(3H, s), 3.08(1H,ddd, J=13, 13, 3Hz), 2.56-2.42(2H, m), 2.28-2.12(2H, m), 2.13(2H, s),1.97-1.61(4H, m), 1.25(1H, ddd, J=13, 13, 5Hz), 1.14(1H, ddd, J=13, 13,5Hz)  48-2 KBr: 2941, CDCl₃: 7.33(1H, dd, J=7, 2Hz), oil 1514, 1252,7.26-7.10(3H, m), 6.89(2H, d,  812, 750 J=9Hz), 6.76(2H, d, J=9Hz),4.62- 4.51(1H, m), 3.30(2H, t, J=7Hz), 3.01-2.93(2H, m), 2.82-2.71(2H,m), 2.78(3H, s), 2.67-2.58(2H, m), 2.57-2.35(4H, m), 2.23-2.07(2H, m),1.92-1.55(8H, m)  49-1 — CDCl₃: 7.56(1H, d, J=3Hz), 7.32- — 7.22(5H, m),7.20(1H, dd, J=9, 3Hz), 6.98(1H, d, J=9Hz), 5.11(1H, s), 4.07(2H, t,J=6Hz), 3.90(3H, s), 3.47(2H, s), 3.23(3H, s), 2.60- 2.49(2H, m),2.44-2.34(2H, m), 2.15(2H, s), 1.92-1.79(2H, m), 1.71-1.49(4H, m),1.39(2H, ddd, J=12, 12, 4Hz), 1.00(3H, t, J=7Hz)  49-2 — CDCl₃*:7.58(1H, d, J=3Hz), — 7.22(1H, dd, J=9, 3Hz), 6.99(1H, d, J=9Hz),5.17(1H, s), 4.07(2H, t, J=6Hz), 3.91(3H, s), 3.24(3H, s), 3.00(2H, ddd,J=12, 12, 3Hz), 2.77- 2.67(2H, m), 2.16(2H, s), 1.91- 1.48(6H, m),1.38-1.24(2H, m), 1.00(3H, t, J=7Hz)  49-3 — CDCl₃*: 7.54(1H, d, J=3Hz),7.22- — 7.13(3H, m), 7.04-6.93(3H, m), 5.27(1H, s), 4.40-4.30(1H, m),4.08(2H, t, J=7Hz), 3.92(3H, s), 3.66(2H, s), 3.62-3.36(2H, m), 3.23(3H,s), 3.03(1H, ddd, J=13, 13, 3Hz), 2.08(2H, s), 1.92- 1.78(2H, m),1.74-1.48(4H, m), 1.19(1H, ddd, 13, 13, 5Hz), 1.05- 0.90(4H, m)  49-4 —CDCl₃*: 7.97-7.93(1H, m), 7.32- — 6.92(6H, m), 5.21(1H, s), 4.40-4.25(3H, m), 3.74-3.30(2H, m), 3.66(2H, s), 3.24(3H, s), 3.10- 2.96(1H,m), 2.08(2H, s), 2.02- 1.82(2H, m), 1.72-1.48(4H, m), 1.30-0.92(5H, m) 49-5 KBr: 3365, CDCl₃*: 7.14(2H, dd, J=9, 6Hz), 129.6-  2953, 2929,7.01-6.90(3H, m), 6.88-6.74(2H, m), 130.8 1508, 1238, 4.66(2H, s),3.98(2H, t, J=6Hz), 1227, 1211 3.91(1H, s), 3.31(2H, t, J=7Hz),2.83-2.66(4H, m), 2.79(3H, s), 2.64-2.52(2H, m), 2.44(2H, ddd, J=11, 11,4Hz), 1.84-1.42(10H, m), 0.98(3H, t, J=7Hz)  50-1 — CDCl₃: 6.80-6.60(3H,m), 5.94(2H, — s), 4.42-4.33(1H, m), 3.85(1H, s), 3.67-3.58(1H, m),3.64(2H, s), 3.42(1H, ddd, J=13, 13, 3Hz), 3.07(1H, ddd, J=13, 13, 3Hz),2.33(2H, s), 1.75-1.57(2H, m), 1.50-1.35(1H, m), 1.46(9H, s), 1.23(1H,ddd, J=13, 13, 5Hz)  50-2 — DMSO-d₆: 6.81(1H, d, J=8Hz), — 6.76(1H, d,J=2Hz), 6.65(1H, dd, J=8, 2Hz), 5.96(2H, s), 4.66(1H, s), 4.08-3.98(1H,m), 3.70-3.18(4H, m), 2.98-2.86(1H, m), 2.31(2H, s), 1.58-1.38(4H, m) 50-3 — CDCl₃*: 7.12-7.07(1H, m), 7.00- — 6.82(2H, m), 6.76-6.69(2H, m),6.67-6.61(1H, m), 5.93(2H, s), 5.32(1H, s), 4.58-4.48(2H, m),4.39-4.27(1H, m), 4.00(2H, t, J=6Hz), 3.59(2H, s), 3.58-3.50(1H, m),3.48-3.33(1H, m), 3.17(3H, s), 3.08-2.96(1H, m), 2.36-2.29(0.5H, m),2.20-2.13(0.5H, m), 2.12- 1.93(2H, m), 1.86-1.44(6H, m), 1.28-1.13(1H,m), 1.08-0.89(1H, m), 1.00(3H, t, J=7Hz)  50-4 liquid film: CDCl₃:7.15(1H, d, J=9Hz), 6.89- oil 2935, 2872, 6.79(2H, m), 6.73(1H, d,J=8Hz), 1498, 1444, 6.69(1H, d, J=2Hz), 6.64(1H, dd, 1246, 1039 J=8,2Hz), 5.92(2H, s), 4.69(2H, s), 3.94(2H, t, J=7Hz), 3.14(2H, t, J=7Hz),2.80-2.38(6H, m), 2.63(3H, s), 1.81-1.60(6H, m), 1.56-1.42(2H, m),0.97(3H, t, J=7Hz)  51-1 — CDCl₃*: 7.33-7.19(10H, m), 6.94(2H, — d,J=9Hz), 6.81(2H, d, J=9Hz), 4.66(1H, d, J=12Hz), 4.38(1H, d, J=12Hz),4.24(1H, s), 3.95(2H, t, J=6Hz), 3.80(1H, s), 3.48(2H, s), 3.28(3H, s),2.68-2.55(2H, m), 2.46-2.25(2H, m), 1.97-1.70(3H, m), 1.60-1.21(5H, m),1.00(3H, t, J=7Hz)  51-2 — CDCl₃*: 7.13(2H, d, J=9Hz), — 6.91(2H, d,J=9Hz), 3.97(2H, t, J=6Hz), 3.75(1H, s), 3.27(3H, s), 3.00(1H, ddd,J=12, 12, 3Hz), 2.88(1H, ddd, J=12, 12, 3Hz), 2.82- 2.70(2H, m),1.85-1.72(3H, m), 1.59-1.14(5H, m), 0.99(3H, t, J=7Hz)  51-3 — CDCl₃:7.32-7.09(7H, m), 6.91(2H, — d, J=8Hz), 4.09(1H, s), 3.97(2H, t, J=6Hz),3.75(1H, d, J=11Hz), 3.28(3H, s), 3.16(1H, d, J=11Hz), 2.87-2.54(6H, m),2.45(1H, ddd, J=11, 11, 5Hz), 2.39-2.27(1H, m), 1.92-1.73(3H, m),1.59-1.42(4H, m), 1.39-1.23(1H, m), 1.00(3H, t, J=7Hz)  51-4 KBr: 1514,CDCl₃*: 7.33-7.16(5H, m), 6.88(2H, 56.6- 1250, 1122, d, J=9Hz), 6.84(2H,d, J=9Hz), 57.5 1043, 831, 3.91(2H, t, J=6Hz), 3.61(1H, dd,  698 J=11,4Hz), 3.31(1H, dd, J=14, 11Hz), 3.09(1H, dd, J=14, 4Hz), 2.92-2.78(4H,m), 2.81(3H, s), 2.71-2.60(2H, m), 2.55-2.39(2H, m), 1.95-1.40(8H, m),0.97(3H, t, J=7Hz)  52-1 — CDCl₃: 7.10(2H, d, J=9Hz), 6.92(2H, — d,J=9Hz), 3.98(2H, t, J=7Hz), 3.56(1H, s), 3.34(3H, s), 3.30(3H, s),3.11-2.98(1H, m), 2.95(1H, ddd, J=12, 12, 3Hz), 2.86-2.74(2H, m),1.90-1.75(3H, m), 1.60-1.38(4H, m), 1.23(1H, ddd, J=13, 13, 5Hz),1.00(3H, t, J=7Hz)  52-2 — CDCl₃*: 7.14(2H, dd, J=9, 5Hz), — 7.10(2H, d,J=9Hz), 6.96(2H, dd, J=9, 9Hz), 6.92(2H, d, J=9Hz), 4.29(1H, s),3.98(2H, t, J=6Hz), 3.34(3H, s), 3.31(3H, s), 2.82- 2.68(4H, m),2.62-2.30(4H, m), 1.98-1.87(1H, m), 1.86-1.74(2H, m), 1.61-1.44(4H, m),1.42-1.26(1H, m), 1.01(3H, t, J=7Hz)  52-3 KBr: 2935, CDCl₃*: 7.16(2H,dd, J=9, 6Hz), 66.8- 1514, 1240, 6.96(2H, dd, J=9, 9Hz), 6.83(2H, d,67.2 1215, 812 J=9Hz), 6.75(2H, d, J=9Hz), 3.91(2H, t, J=6Hz), 3.51(1H,dd, J=14, 3Hz), 3.40(3H, s), 3.28(1H, dd, J=14, 8Hz), 3.20(1H, dd, J=8,3Hz), 2.92(3H, s), 2.87-2.74(4H, m), 2.64-2.54(2H, m), 2.47-2.33(2H, m),1.84-1.40(8H, m), 0.97(3H, t, J=7Hz)  53-1 — CDCl₃*: 7.13(2H, dd, J=9,5Hz), — 7.13(2H, d, J=9Hz), 6.95(2H, dd, J=9, 9Hz), 6.91(2H, d, J=9Hz),4.11(1H, s), 3.97(2H, t, J=6Hz), 3.74(1H, d, J=10Hz), 3.28(3H, s),3.20(1H, d, J=10Hz), 2.80-2.65(4H, m), 2.60-2.50(1H, m), 2.58(1H, s),2.44(1H, ddd, J=11, 11, 5Hz), 2.31(1H, ddd, J=12, 12, 2Hz), 1.92-1.72(3H, m), 1.59-1.42(4H, m), 1.37-1.22(1H, m), 1.00(3H, t, J=7Hz) 53-2 KBr: 2935, CDCl₃*: 7.16(2H, dd, J=9, 5Hz), 67.1- 1512, 1242,6.96(2H, dd, J=9, 9Hz), 6.87(2H, d, 68.2 1225, 827 J=9Hz), 6.83(2H, d,J=9Hz), 3.91(2H, t, J=6Hz), 3.60(1H, dd, J=11, 4Hz), 3.31(1H, dd, J=13,11Hz), 3.09(1H, dd, J=13, 4Hz), 2.87-2.74(4H, m), 2.81(3H, s),2.64-2.55(1H, m), 2.63(1H, s), 2.48-2.33(2H, m), 1.95-1.84(1H, m),1.80-1.67(3H, m), 1.60(2H, dd, J=8, 3Hz), 1.55-1.40(2H, m), 0.97(3H, t,J=7Hz) 54 KBr: 1512, CDCl₃*: 7.41-7.22(5H, m), 6.92(2H, 104.0-  1470,1244, d, J=9Hz), 6.85(2H, d, J=9Hz), 104.8 1070, 700 4.74(1H, dd, J=10,4Hz), 3.92(2H, t, J=6Hz), 3.29(2H, t, J=6Hz), 2.97-2.86(1H, m),2.81-2.68(1H, m), 2.78(3H, s), 2.62-2.40(4H, m), 1.80-1.40(10H, m),0.97(3H, t, J=7Hz) 55 KBr: 2939, CDCl₃*: 7.34(2H, dd, J=9, 6Hz), 92.8-1512, 1246, 7.02(2H, dd, J=9, 9Hz), 6.92(2H, d, 94.5 1223, 835 J=9Hz),6.85(2H, d, J=9Hz), 4.70(1H, dd, J=10, 3Hz), 3.92(2H, t, J=6Hz),3.29(2H, t, J=6Hz), 2.95-2.84(1H, m), 2.82-2.68(2H, m), 2.78(3H, s),2.62-2.36(4H, m), 1.82-1.40(10H, m), 0.97(3H, t, J=7Hz) 56 KBr: 3408,CDCl₃*: 7.33-7.20(5H, m), 7.07(2H, 89.7- 2953, 2931, d, J=9Hz), 6.90(2H,d, J=9Hz), 90.6 1637, 1510, 3.97(2H, t, J=6Hz), 3.81(2H, t, 1248 J=7Hz),3.51(2H, s), 2.92(1H, s), 2.63-2.55(2H, m), 2.37(2H, ddd, J=11, 11,5Hz), 1.83-1.43(10H, m), 1.80(3H, s), 0.98(3H, t, J=7Hz) 57 KBr: 3415,CDCl₃: 7.15(2H, dd, J=9, 5Hz), 121.6-  2953, 2933, 7.08(2H, d, J=9Hz),6.96(2H, dd, 122.1 1637, 1512, J=9, 9Hz), 6.92(2H, d, J=9Hz), 1250, 12193.97(2H, t, J=7Hz), 3.83(2H, t, J=7Hz), 3.08(1H, s), 2.85-2.40(8H, m),1.85-1.44(10H, m), 1.82(3H, s), 0.99(3H, t, J=7Hz)  58-1 — CDCl₃:7.04(2H, d, J=9Hz), 6.92(2H, — d, J=9Hz), 5.38(1H, s), 3.80- 3.65(2H,m), 3.30-3.10(2H, m), 3.24(3H, s), 2.15(2H, s), 1.85- 1.74(2H, m),1.70-1.40(4H, m), 1.43(9H, s), 1.32-1.28(2H, m), 0.97(3H, t, J=7Hz) 58-2 — CDCl₃: 7.05(2H, d, J=9Hz), 6.90(2H, — d, J=9Hz), 3.97(2H, t,J=7Hz), 3.87-3.67(2H, m), 3.22(3H, s), 3.09-2.89(2H, m), 3.04(3H, s),2.34(2H, s), 1.85-1.60(6H, m), 1.60-1.40(2H, m), 1.44(9H, s), 0.99(3H,t, J=7Hz)  58-3 — CDCl₃: 7.06(2H, d, J=9Hz), 6.90(2H, — d, J=9Hz),3.97(2H, t, J=7Hz), 3.22(3H, s), 3.05(3H, s), 2.92- 2.75(4H, m),2.34(2H, s), 1.85- 1.60(6H, m), 1.58-1.44(2H, m), 0.99(3H, t, J=7Hz) 58-4 — CDCl₃*: 7.35-7.20(5H, m), 7.05(2H, — d, J=9Hz), 6.88(2H, d,J=9Hz), 3.96(2H, t, J=6Hz), 3.46(2H, s), 3.22(3H, s), 3.05(3H, s), 2.60-2.48(2H, m), 2.33(2H, s), 2.30- 2.16(2H, m), 1.84-1.62(6H, m),1.60-1.43(2H, m), 0.9(3H, t, J=7Hz)  58-5 liquid film: CDCl₃:7.35-7.25(5H, m), 6.82(2H, oil 2937, 2871, d, J=9Hz), 6.69(2H, d,J=9Hz), 2817, 1514, 3.90(2H, t, J=7Hz), 3.49(2H, s), 1242, 10783.33-3.27(2H, m), 3.17(3H, s), 2.82(3H, s), 2.62-2.51(2H, m),2.33-2.20(2H, m), 1.85-1.40(10H, m), 0.96(3H, t, J=7Hz) 59 liquid film:CDCl₃: 7.36-7.21(5H, m), 6.84(2H, oil 2935, 1514, d, J=9Hz), 6.81(2H, d,J=9Hz), 1244, 1072, 3.90(2H, t, J=7Hz), 3.53(2H, s),  814, 700 3.17(2H,s), 2.92(3H, s), 2.75- 2.65(2H, m), 2.42-2.30(2H, m), 2.00(1H, s),1.78-1.40(8H, m), 0.96(3H, t, J=7Hz) 60 KBr: 2943, CDCl₃*: 7.37(1H, ddd,J=7, 7, 2Hz), oil 1512, 1242, 7.28-7.17(1H, m), 7.09(1H, ddd,  825, 754J=7, 7, 1Hz), 7.07-6.98(1H, m), 6.88(2H, d, J=9Hz), 6.83(2H, d, J=9Hz),3.98-3.83(1H, m), 3.91(2H, t, J=6Hz), 3.60(2H, s), 3.28(2H, t, J=7Hz),2.77(3H, s), 2.69-2.58(2H, m), 2.45(2H, ddd, J=11, 11, 4Hz),1.80-1.40(10H, m), 0.96(3H, t, J=7Hz) 61 KBr: 2937, CDCl₃*:7.23-7.03(4H, m), 6.88(2H, oil 1512, 1470, d, J=10Hz), 6.83(2H, d,J=10Hz), 1242, 814 3.91(2H, t, J=7Hz), 3.85(1H, s), 3.48(2H, s),3.28(2H, t, J=7Hz), 2.77(3H, s), 2.67-2.57(2H, m), 2.43-2.30(2H, m),2.34(3H, s), 1.80-1.40(10H, m), 0.96(3H, t, J=7Hz) 62 KBr: 2943, CDCl₃*:7.32-7.23(1H, m), 7.18- 77.0- 2870, 1512, 7.10(3H, m), 6.88(2H, d,J=9Hz), 78.0 1475, 1242 6.83(2H, d, J=9Hz), 3.91(2H, t, J=7Hz), 3.47(2H,s), 3.29(2H, t, J=7Hz), 2.78(3H, s), 2.66-2.53(2H, m), 2.40(2H, ddd,J=11, 11, 3Hz), 2.35(3H, s), 1.82-1.40(10H, m), 0.96(3H, t, J=7Hz) 63KBr: 2939, CDCl₃*: 7.09(1H, dd, J=12Hz, 2Hz), 54.6- 1516, 1275,7.03-6.97(1H, m), 6.93-6.86(3H, m), 56.6 1242, 1221, 6.83(2H, d, J=9Hz),3.91(2H, t, 1122, 1032 J=6Hz), 3.88(3H, s), 3.45(2H, s), 3.28(2H, t,J=7Hz), 2.77(3H, s), 2.65-2.54(2H, m), 2.37(2H, ddd, J=11, 11, 3Hz),1.80-1.56(8H, m), 1.56-1.40(2H, m), 0.96(3H, t, J=7Hz)  64-1 — CDCl₃:7.34-7.20(5H, m), 7.00(4H, — s), 5.26(1H, s), 3.47(2H, s), 3.24(3H, s),2.56-2.46(2H, m), 2.39(2H, ddd, J=11, 11, 3Hz), 2.17(2H, s), 1.71(2H, q,J=8Hz), 1.70-1.62(2H, m), 1.39(2H, ddd, J=12, 12, 4Hz), 1.31(6H, s),1.03(3H, t, J=7Hz)  64-2 KBr: 3363, CDCl₃: 7.35-7.22(5H, m), 6.87(2H,52.8- 2974, 2937, d, J=9Hz), 6.75(2H, d, J=9Hz), 53.2 2922, 2810,3.52(2H, s), 3.36(2H, t, J=7Hz), 1508, 1236, 3.07(1H, br. s), 2.82(3H,s), 2.67-  737 2.57(2H, m), 2.43-2.32(2H, m), 1.73-1.59(8H, m), 1.21(6H,s), 1.00(3H, t, J=7Hz)  65-1 — CDCl₃: 7.33-7.19(5H, m), 6.90(1H, — d,J=2Hz), 6.87(1H, d, J=8Hz), 6.73(1H, dd, J=8, 2Hz), 5.20(1H, s),5.19(2H, s), 4.04(2H, t, J=7Hz), 3.51(3H, s), 3.47(2H, s), 3.23(3H, s),2.58-2.49(2H, m), 2.39(2H, ddd, J=11, 11, 2Hz), 2.19(2H, s),1.89-1.79(2H, m), 1.70-1.61(2H, m), 1.58-1.44(2H, m), 1.40(2H, ddd,J=13, 13, 4Hz), 1.00(3H, t, J=7Hz)  65-2 liquid film: CDCl₃:7.37-7.20(5H, m), 6.75(1H, oil 3398, 2956, d, J=9Hz), 6.55(1H, d,J=3Hz), 2939, 2872, 6.35(1H, dd, J=9, 3Hz), 5.65(1H, 2819, 1516, br. s),3.98(2H, t, J=7Hz), 3.52(2H, 1252, 1217, s), 3.31(2H, t, J=7Hz),2.78(3H,  976, 743, 700 s), 2.68-2.57(2H, m), 2.44-2.32(2H, m),1.81-1.57(8H, m), 1.54-1.41(2H, m), 0.97(3H, t, J=7Hz)  66-1 — CDCl₃:7.34-7.19(5H, m), 7.08- — 7.01(1H, m), 6.73-6.66(2H, m), 5.10(1H, s),3.96(2H, t, J=6Hz), 3.47(2H, s), 3.20(3H, s), 2.60- 2.48(2H, m),2.39(2H, ddd, J=12, 12, 3Hz), 2.15(2H, s), 1.85- 1.23(8H, m), 1.00(3H,t, J=7Hz)  66-2 liquid film: CDCl₃: 7.35-7.20(5H, m), 7.06- oil 2935,1510, 6.98(1H, m), 6.67-6.58(2H, m), 1454, 1286, 4.87(1H, s), 3.90(2H,t, J=7Hz), 1159 3.52(2H, s), 3.18(2H, t, J=6Hz), 2.70(3H, s),2.63-2.55(2H, m), 2, 41(2H, ddd, J=11, 11, 3Hz), 1.80- 1.40(10H, m),0.97(3H, t, J=7Hz)  67-1 — CDCl₃: 7.34-7.19(5H, m), 6.92(2H, — d,J=9Hz), 6.90(2H, d, J=9), 5.40(1H, s), 5.04-4.90(1H, m), 3.98(2H, t,J=6Hz), 3.47(2H, s), 2.58-2.50(2H, m), 2.38(2H, ddd, J=12, 12, 2Hz),2.02(2H, s), 1.85- 1.74(2H, m), 1.68-1.58(2H, m), 1.59-1.46(2H, m),1.36(2H, ddd, J=12, 12, 4Hz), 1.03(6H, d, J=7Hz), 1.01(3H, t, J=7Hz) 67-2 KBr: 3331, CDCl₃: 7.35-7.20(5H, m), 6.99(2H, 79.4- 2960, 2935, d,J=9Hz), 6.83(2H, d, J=9Hz), 79.7 2872, 2818, 5.74(1H, s), 3.92(2H, t,J=7Hz), 1510, 1244, 3.51(2H, s), 3.44-3.34(1H, m), 1115, 825, 3.25(2H,t, J=6Hz), 2.64-2.53(2H,  739 m), 2.38(2H, ddd, J=11, 11, 3Hz),1.80-1.43(10H, m), 1.03(6H, d, J=7Hz), 0.97(3H, t, J=7Hz) 68 liquidfilm: CDCl₃: 7.35-7.21(5H, m), 6.86(2H, oil 2962, 2937, d, J=9Hz),6.83(2H, d, J=9Hz), 2877, 2810, 4.04-3.94(1H, m), 3.52(2H, s), 1508,1238 3.29(2H, t, J=7Hz), 2.77(3H, s),  972, 814, 698 2.67-2.56(2H, m),2.38(2H, ddd, J=11, 11, 4Hz), 1.73-1.57(10H, m), 0.95(6H, t, J=7Hz) 69KBr: 2951, CDCl₃: 7.35-7.20(5H, m), 6.88(2H, amorphous 1515, 1246, d,J=9Hz), 6.83(2H, d, J=9Hz),  812, 700 3.93(2H, t, J=7Hz), 3.52(2H, s),3.28(2H, t, J=7Hz), 2.77(3H, s), 2.66-2.56(2H, m), 2.38(2H, ddd, J=11,11, 4Hz), 1.90-1.74(1H, m), 1.72-1.56(8H, m), 0.95(6H, d, J=7Hz) 70liquid film: CDCl₃: 7.35-7.20(5H, m), 6.89(2H, oil 2929, 1514, d,J=9Hz), 6.85(2H, d, J=9Hz), 1470, 1244, 3.98(2H, t, J=7Hz), 3.52(2H, s), 814 3.29(2H, t, J=7Hz), 2.77(3H, s), 2.67-2.57(2H, m), 2.38(2H, ddd,J=11, 11, 4Hz), 1.75-1.55(8H, m), 0.92-0.77(1H, m), 0.51-0.43(2H, m),0.14-0.07(2H, m) 71 liquid film: CDCl₃: 7.35-7.21(5H, m), 6.87(2H, oil2949, 2920, d, J=9Hz), 6.84(2H, d, J=9Hz), 1512, 1242, 5.90(1H, ddt,J=17, 10, 7Hz), 5.20- 1041, 825 5.06(2H, m), 3.97(2H, t, J=7Hz),3.52(2H, s), 3.29(2H, t, J=7Hz), 2.78(3H, s), 2.66-2.57(2H, m),2.56-2.48(2H, m), 2.38(2H, ddd, J=11, 11, 4Hz), 1.73-1.54(6H, m)  72-1 —CDCl₃*: 6.88(2H, d, J=9Hz), — 6.83(2H, d, J=9Hz), 4.50-4.36(1H, m),3.30(2H, t, J=7Hz), 3.00(2H, ddd, J=12, 12, 3Hz), 2.84(2H, ddd, J=12, 4,4Hz), 2.78(3H, s), 1.75- 1.48(6H, m), 1.31(6H, d, J=6Hz)  72-2 KBr:1510, CDCl₃: 7.26(4H, s), 6.87(2H, d, 96.9- 1244, 1132, J=9Hz), 6.83(2H,d, J=9Hz), 4.49- 97.1 1082, 837 4.36(1H, m), 3.93(1H, br. s), 3.48(2H,s), 3.29(2H, t, J=7Hz), 2.77(3H, s), 2.63-2.53(2H, m), 2.37(2H, ddd,J=11, 11, 3Hz), 1.73- 1.55(6H, m), 1.31(6H, d, J=6Hz) 73 KBr: 1510,CDCl₃: 7.43(2H, d, J=8Hz), 7.20(2H, 104.3-  1244, 1132, d, J=8Hz),6.87(2H, d, J=9Hz), 105.0 1012 6.83(2H, d, J=9Hz), 4.49-4.37(1H, m),3.93(1H, br. s), 3.46(2H, s), 3.29(2H, t, J=7Hz), 2.77(3H, s),2.63-2.53(2H, m), 2.37(2H, ddd, J=11, 11, 3Hz), 1.73-1.55(6H, m),1.31(6H, d, J=6Hz) 74 KBr: 1510, CDCl₃: 7.56(2H, d, J=8Hz), 7.45(2H,109.9-  1331, 1153, d, J=8Hz), 6.88(2H, d, J=9Hz), 110.6 1124, 11116.83(2H, d, J=9Hz), 4.50-4.36(1H, m), 4.00(1H, br. s), 3.57(2H, s),3.29(2H, t, J=7Hz), 2.78(3H, s), 2.64-2.54(2H, m), 2.41(2H, ddd, J=11,11, 3Hz), 1.74-1.55(6H, m), 1.31(6H, d, J=6Hz) 75 KBr: 2958, CDCl₃:7.23(2H, d, J=8Hz), 7.17(2H, 75.5- 1510, 1244, d, J=8Hz), 6.86(2H, d,J=9Hz), 75.9  829 6.82(2H, d, J=9Hz), 4.49-4.35(1H, m), 3.78(1H, br. s),3.49(2H, s), 3.29(2H, t, J=7Hz), 2.97-2.82(1H, m), 2.78(3H, s),2.67-2.57(2H, m), 2.37(2H, ddd, J=10, 10, 4Hz), 1.73- 1.56(6H, m),1.30(6H, d, J=6Hz), 1.24(6H, d, J=7Hz) 76 KBr: 1510, CDCl₃: 7.23(2H, d,J=9Hz), 6.89- 50.8- 1257, 1244, 6.78(6H, m), 4.48-4.36(1H, m), 52.4  8293.80(3H, s), 3.46(2H, s), 3.29(2H, t, J=7Hz), 2.77(3H, s), 2.65-2.55(2H, m), 2.35(2H, ddd, J=11, 11, 4Hz), 1.30(6H, d, J=6Hz) 77 KBr:1510, CDCl₃: 7.22(1H, dd, J=8, 8Hz), 45.1- 1263, 1242, 6.93-6.77(7H, m),4.49-4.86(1H, m), 46.5 1136 3.81(3H, s), 3.50(2H, s), 3.29(2H, t,J=7Hz), 2.78(3H, s), 2.67- 2.57(2H, m), 2.38(2H, ddd, J=11, 11, 4Hz),1.73-1.57(6H, m), 1.30(6H, d, J=6Hz) 78 KBr: 1510, CDCl₃: 7.28(2H, dd,J=9, 5Hz), 69.2- 1244, 1217, 6.99(2H, dd, J=9, 9Hz), 6.87(2H, d, 70.0 833 J=9Hz), 6.83(2H, d, J=9Hz), 4.49- 4.36(1H, m), 3.92(1H, br. s),3.48(2H, s), 3.29(2H, t, J=7Hz), 2.77(3H, s), 2.64-2.55(2H, m), 2.37(2H,ddd, J=11, 11, 4Hz), 1.75- 1.55(6H, m), 1.31(6H, d, J=6Hz) 79 KBr: 3504,CDCl₃: 7.60(2H, d, J=8Hz), 7.45(2H, 108.1-  2933, 2229, d, J=8Hz),6.88(2H, d, J=9Hz), 109.5 1510, 1242 6.83(2H, d, J=9Hz), 4.50-4.37(1H,m), 3.56(2H, s), 3.29(2H, t, J=7Hz), 2.77(3H, s), 2.62-2.53(2H, m),2.41(2H, ddd, J=11, 11, 3Hz), 1.75-1.55(6H, m), 1.31(6H, d, J=6Hz) 80KBr: 1510, CDCl₃: 7.85-7.72(4H, m), 7.52- 76.2- 1244, 1138, 7.41(3H, m),6.86(2H, d, J=9Hz), 76.8  960, 818 6.82(2H, d, J=9Hz), 4.49-4.36(1H, m),3.68(2H, s), 3.29(2H, t, J=7Hz), 2.78(3H, s), 2.72-2.62(2H, m), 2.44(2H,ddd, J=10, 10, 5Hz), 1.74-1.58(6H, m), 1.30(6H, d, J=6Hz) 81 liquidfilm: CDCl₃: 7.21(2H, d, J=8Hz), 6.86(2H, oil 2976, 2935, d, J=9Hz),6.83(2H, d, J=8Hz), 1510, 1371, 6.82(2H, d, J=9Hz), 4.58-4.35(2H, 1240,957 m), 3.46(2H, s), 3.29(2H, t, J=7Hz), 2.78(3H, s), 2.67-2.57(2H, m),2.43-2.41(2H, m), 1.72-1.56(6H, m), 1.33(6H, d, J=6Hz), 1.30(6H, d,J=6Hz) 82 liquid film: CDCl₃: 7.53(1H, dd, J=8, 1Hz), oil 2937, 1510,7.49-7.44(1H, m), 7.27(1H, ddd, 1240, 1113 J=8, 8, 1Hz), 7.10(1H, ddd,J=8, 8, 2Hz), 6.87(2H, d, J=9Hz), 6.83(2H, d, J=9Hz), 4.50-4.35(1H, m),3.84(1H, br. s), 3.62(2H, s), 3.30(2H, t, J=7Hz), 2.79(3H, s),2.70-2.60(2H, m), 2.51(2H, ddd, J=10, 10, 4Hz), 1.76-1.55(6H, m),1.31(6H, d, J=6Hz) 83 liquid film: CDCl₃: 7.50(1H, dd, J=1Hz), oil 2935,1510, 7.37(1H, ddd, J=8, 2, 2Hz), 7.28- 1238, 1113 7.22(1H, m), 7.17(1H,dd, J=8, 8Hz), 6.87(2H, d, J=9Hz), 6.83(2H, d, J=9Hz), 4.48-4.37(1H, m),3.49(2H, s), 3.29(2H, t, J=7Hz), 2.78(3H, s), 2.65-2.54(2H, m), 2.39(2H,ddd, J=11, 11, 4Hz), 2.75- 2.50(6H, m), 1.31(6H, d, J=6Hz) 84 KBr: 2933,CDCl₃: 8.17(2H, d, J=9Hz), 7.51(2H, 62.5- 1518, 1344, d, J=9Hz),6.89(2H, d, J=9Hz), 63.1 1242, 1107, 6.83(2H, d, J=9Hz), 4.50-4.36(1H, 822 m), 3.61(2H, s), 3.29(2H, t, J=7Hz), 2.78(3H, s), 2.62-2.54(2H, m),2.47(2H, ddd, J=11, 11, 4Hz), 1.75-1.50(6H, m), 1.31(6H, d, J=6Hz) 85KBr: 1510, CDCl₃: 7.62-7.58(1H, m), 7.53- 60.8- 1327, 1244, 7.47(2H, m),7.42(1H, dd, J=8Hz), 61.1 1174 1134 6.87(2H, d, J=9Hz), 6.83(2H, d,J=9Hz, 4.50-4.37(1H, m), 3.94(1H, br. s), 3.56(2H, s), 3.29(2H, t,J=7Hz), 2.78(3H, s), 2.63-2.54(2H, m), 2.41(2H, ddd, J=11, 11, 4Hz),1.74-1.56(6H, m), 1.31(6H, d, J=6Hz) 86 KBr: 1722, CDCl₃: 7.98(2H, d,J=8Hz), 7.40(2H, 78.8- 1510, 1281, d, J=9Hz), 6.87(2H, d, J=9Hz), 80.81244, 1113 6.82(2H, d, J=9Hz), 4.50-4.36(1H, m), 3.91(3H, s), 3.56(2H,s), 3.29(2H, t, J=7Hz), 2.77(3H, s), 2.64-2.54(2H, m), 2.40(2H, ddd,J=11, 11, 4Hz), 1.75-1.50(6H, m), 1.30(6H, d, J=6Hz) 87 KBr: 1510,CDCl₃: 7.38-7.28(1H, m), 6.92- 77.6- 1246, 1136, 6.73(6H, m),4.50-4.37(1H, m), 77.9  852, 825 3.93(1H, br. s), 3.55(2H, s), 3.28(2H,t, J=7Hz), 2.77(3H, s), 2.66-2.56(2H, m), 2.43(2H, ddd, J=11, 11, 4Hz),1.73-1.55(6H, m), 1.31(6H, d, J=6Hz) 88 KBr: 1508, CDCl₃: 7.56(1H, dd,J=7, 2Hz), 58.8- 1317, 1252, 7.52-7.46(1H, m), 7.13(1H, dd, J=9, 62.81240, 1173, 9Hz), 6.88(2H, d, J=9Hz), 6.83(2H, 1151 d, J=9Hz),4.50-4.37(1H, m), 4.03(1H, br. s), 3.51(2H, s), 3.29(2H, t, J=7Hz),2.78(3H, s), 2.62-2.52(2H, m), 2.40(2H, ddd, J=11, 11, 3Hz),1.74-1.56(6H, m), 1.31(6H, d, J=6Hz) 89 KBr: 1510, CDCl₃: 7.34(2H, d,J=9Hz), 7.15(2H, 84.7- 1281, 1244, d, J=9Hz), 6.87(2H, d, J=9Hz), 85.11225, 1153 6.83(2H, d, J=9Hz), 4.50-4.37(1H, m), 3.94(1H, br. s),3.51(2H, s), 3, 29(2H, t, J=7Hz), 2, 78(3H, s), 2.63-2.55(2H, m),2.39(2H, ddd, J=11, 11, 3Hz), 1.74-1.55(6H, m), 1.31(6H, d, J=6Hz) 90KBr: 2976, CDCl₃: 7.20(1H, dd, J=9, 9Hz), 65.1- 1510, 1246, 6.86(2H, d,J=9Hz), 6.82(2H, d, 66.1 1113, 829 J=9Hz), 6.63(1H, dd, J=8, 2Hz),6.56(1H, dd, J=12, 2Hz), 4.55- 4.36(2H, m), 3.79(1H, br. s), 3.52(2H,s), 3.28(2H, t, J=7Hz), 2.77(3H, s), 2.68-2.58(2H, m), 2.41(2H, ddd,J=11, 11, 4Hz), 1.72- 1.55(6H, m), 1.33(6H, 6, J=6Hz), 1.30(6H, d,J=6Hz) 91 KBr: 1514, CDCl₃*: 7.62-7.52(4H, m), 7.47- 66.9- 1244, 1117,7.28(5H, m), 6.86(2H, d, J=9Hz), 68.0  758, 694 6.83(2H, d, J=9Hz),4.50-4.36(1H, m), 3.57(2H, s), 3.30(2H, t, J=7Hz), 2.78(3H, s),2.72-2.60(2H, m), 2.42(2H, ddd, J=11, 11, 4Hz), 1.76-1.52(6H, m) 92liquid film: CDCl₃*: 7.37-7.25(4H, m), 7.12- oil 2937, 1510, 6.92(5H,m), 6.86(2H, d, J=9Hz), 1489, 1238, 6.83(2H, d, J=9Hz), 4.48-4.35(1H,1115 m), 3.49(2H, s), 3.30(2H, t, J=7Hz), 2.78(3H, s), 2.68-2.57(2H, m),2.38(2H, ddd, J=11, 11, 4Hz), 1.73-1.52(6H, m), 1.31(6H, d, J=6Hz) 93KBr: 1510, CDCl₃*: 7.32-7.18(3H, m), 6.86(2H, 99.8- 1483, 1244, d,J=9Hz), 6.82(2H, d, J=9Hz), 100.9 1117, 825 4.50-4.35(1H, m), 3.91(1H,br. s), 3.54(2H, s), 3.28(2H, t, J=6Hz), 2.77(3H, s), 2.66-2.55(2H, m),2.43(2H, ddd, J=11, 11, 3Hz), 1.75- 1.50(6H, m), 1.30(6H, d, J=6Hz) 94KBr: 1510, CDCl₃*: 7.30-6.90(4H, m), 6.87(2H, 52.5- 1254, 1246, d,J=9Hz), 6.82(2H, d, J=9Hz), 54.6 1130, 1119, 4.50-4.35(1H, m), 3.52(2H,s),  955 3.29(2H, t, J=7Hz), 2.78(3H, s), 2.67-2.55(2H, m),2.47-2.33(2H, m), 1.73-1.60(6H, m), 1.31(6H, d, J=6Hz) 95 KBr: 1510,CDCl₃: 7.41-7.33(1H, m), 7.26- amorphous 1244, 1117, 6.98(3H, m),6.86(2H, d, J=9Hz),  754 6.82(2H, d, J=9Hz), 4.49-4.36(1H, m), 3.60(2H,s), 3.29(2H, t, J=7Hz), 2.77(3H, s), 2.70-2.60(2H, m), 2.45(2H, ddd,J=11, 11, 4Hz), 1.72-1.57(6H, m), 1.31(6H, d, J=6Hz) 96 KBr: 2924,CDCl₃*: 7.36-7.19(3H, m), 7.09(1H, oil 1510, 1261, d, J=8Hz), 6.87(2H,d, J=9Hz), 1217, 1167 6.83(2H, d, J=9Hz), 4.50-4.35(1H, m), 3.53(2H, s),3.29(2H, t, J=6Hz), 2.78(3H, s), 2.64-2.54(2H, m), 2.40(2H, ddd, J=11,11, 4Hz), 1.74-1.52(6H, m), 1.31(6H, d, J=6Hz) 97 KBr: 2927, CDCl₃:7.57-7.50(1H, m), 7.30- oil 1510, 1255 7.19(3H, m), 6.87(2H, d, J=9Hz),1225, 1165 6.83(2H, d, J=9Hz), 4.49-4.36(1H, m), 3.59(2H, s), 3.29(2H,t, J=7Hz), 2.78(3H, s), 2.65-2.55(2H, m), 2.45(2H, ddd, J=11, 11, 4Hz),1.74-1.53(6H, m), 1.31(6H, d, J=6Hz) 98 liquid film: CDCl₃:7.36-7.33(1H, m), 7.26- oil 2937, 1510, 7.17(3H, m), 6.87(2H, d, J=9Hz),1240, 1115 6.83(2H, d, J=9Hz), 4.50-4.36(1H, m), 3.49(2H, s), 3.29(2H,t, J=7Hz), 2.78(3H, s), 2.65-2.55(2H, m), 2.39(2H, ddd, J=11, 11, 4Hz),1.73-1.57(6H, m), 1.31(6H, d, J=6Hz) 99 KBr: 2924, CDCl₃: 7.49-7.44(1H,m), 7.36- oil 1510, 1240, 7.32(1H, m), 7.28-7.14(2H, m), 1115 6.87(2H,d, J=9Hz), 6.83(2H, d, J=9Hz), 4.50-4.36(1H, m), 3.64(2H, s), 3.30(2H,t, J=7Hz), 2.79(3H, s), 2.70-2.60(2H, m), 2.50(2H, ddd, J=11, 11, 4Hz),1.75-1.55(6H, m), 1.31(6H, d, J=6Hz) 100  liquid film: CDCl₃:7.68-7.65(1H, m), 7.58- oil 2937, 2229, 7.51(2H, m), 7.41(1H, dd, J=8,1510, 1238, 8Hz), 6.88(2H, d, J=9Hz), 6.83(2H, 1115 d, J=9Hz),4.50-4.36(1H, m), 3, 53(2H, s), 3.29(2H, t, J=7Hz), 2.78(3H, s),2.62-2.52(2H, m), 2.41(2H, ddd, J=11, 11, 3Hz), 1.74- 1.56(6H, m),1.31(6H, d, J=6Hz) 101  liquid film: CDCl₃*: 7.66-7.61(1H, m), 7.56- oil2935, 2224, 7.51(2H, m), 7.39-7.29(1H, m), 1510, 1238, 6.87(2H, d,J=9Hz), 6.83(2H, d, 1115 J=9Hz), 4.50-4.35(1H, m), 3.72(2H, s), 3.29(2H,t, J=7Hz), 2.78(3H, s), 2.66-2.45(4H, m), 1.75-1.55(6H, m), 1.31(6H, d,J=6Hz) 102  liquid film: CDCl₃*: 7.80(1H, d, J=8Hz), oil 1510, 1313,7.61(1H, d, J=8Hz), 7.50(1H, dd, 1240, 1159, J=8, 8Hz), 7.31(1H, dd,J=8, 8Hz), 1120 6.87(2H, d, J=9Hz), 6.83(2H, d, J=9Hz), 4.50-4.35(1H,m), 3.67(2H, s), 3.31(2H, t, J=7Hz), 2.79(3H, s), 2.64-2.52(2H, m),2.47(2H, ddd, J=11, 11, 5Hz), 1.75-1.55(6H, m), 1.31(6H, d, J=6Hz) 103 liquid film: CDCl₃*: 7.37-7.31(1H, m), 7.27- oil 1510, 1493, 7.18(1H,m), 6.96-6.78(6H, m), 1466, 1240, 4.50-4.35(1H, m), 3.81(3H, s), 11173.58(2H, s), 3.30(2H, t, J=7Hz), 2.78(3H, s), 2.72-2.61(2H, m),2.50-2.37(2H, m), 1.72-1.58(6H, m), 1.30(6H, d, J=6Hz) 104  liquid film:CDCl₃: 8.22(1H, dd, J=2, 2Hz), oil 1527, 1510, 8.13-8.08(1H, m),7.69-7.64(1H, m), 1350, 1240, 7.47(1H, dd, J=8, 8Hz), 6.88(2H, d, 1115J=9Hz), 6.83(2H, d, J=9Hz), 4.50- 4.36(1H, m), 3.61(2H, s), 3.29(2H, t,J=7Hz), 2.78(3H, s), 2.60(2H, ddd, J=11, 4, 4Hz), 2.44(2H, ddd, J=11,11, 4Hz), 1.74-1.56(6H, m), 1.31(6H, d, J=6Hz) 105  KBr: 1527, CDCl₃:7.79(1H, dd, J=8, 1Hz), oil 1510, 1367, 7.59(1H, dd, J=8, 2Hz), 7.52(1H,1240, 1115 ddd, J=8, 8, 1Hz), 7.38(1H, ddd, J=8, 8, 2Hz), 6.86(2H, d,J=9Hz), 6.83(2H, d, J=9Hz), 4.49-4.36(1H, m), 3.80(2H, s), 3.23(2H, t,J=7Hz), 2.77(3H, s), 2.56-2.45(2H, m), 2.44(2H, ddd, J=11, 11, 3Hz),1.67(2H, t, J=7Hz), 1.65-1.50(4H, m), 1.31(6H, d, J=6Hz) 106  KBr: 1714,CDCl₃: 7.99(2H, d, J=8Hz), 7.40(2H, 50.3- 1510, 1277, d, J=8Hz),6.88(2H, d, J=9Hz), 51.6 1244, 1113 6.82(2H, d, J=9Hz), 4.49-4.36(1H,m), 4.37(2H, q, J=7Hz), 3.57(2H, s), 3.29(2H, t, J=7Hz), 2.78(3H, s),2.64-2.55(2H, m), 2.40(2H, ddd, J=11, 11, 3Hz), 1.74-1.48(6H, m),1.39(3H, t, J=7Hz), 1.31(6H, d, J=6Hz) 107  liquid film: CDCl₃*:7.25-7.15(1H, m), 7.00- oil 1510, 1238, 6.75(6H, m), 4.49-4.36(1H, m),1113, 957, 3.80(1H, br. s), 3.74(2H, s),  700 3.29(2H, t, J=7Hz),2.78(3H, s), 2.74-2.58(2H, m), 2.50-2.37(2H, m), 1.80-1.48(6H, m),1.30(6H, d, J=6Hz) 108  liquid film: CDCl₃: 7.32-7.24(1H, m), 7.16- oil1510, 1238, 7.08(1H, m), 7.06(1H, dd, J=5, 1113, 957 1Hz), 6.87(2H, d,J=9Hz), 6.83(2H, d, J=9Hz), 4.49-4.37(1H, m), 3.88(1H, br. s), 3.55(2H,s), 3.29(2H, t, J=7Hz), 2.78(3H, s), 2.70-2.57(2H, m), 2.37(2H, ddd,J=11, 11, 4Hz), 1.70-1.48(6H, m), 1.31(6H, d, J=6Hz) 109  KBr: 1510,CDCl₃: 7.25(2H, d, J=8Hz), 7.20(2H, 66.2- 1244, 1115, d, J=8Hz),6.87(2H, d, J=9Hz), 68.0  949, 835 6.82(2H, d, J=9Hz), 4.50-4.36(1H, m),3.48(2H, s), 3.29(2H, t, J=7Hz), 2.77(3H, s), 2.66-2.56(2H, m), 2.48(3H,s), 2.37(2H, ddd, 11, 11, 4Hz), 1.73-1.57(6H, m), 1.30(6H, d, J=6Hz)110  liquid film: CDCl₃: 7.67(1H, d, J=8Hz), 7.44- oil 2937, 1724,7.37(2H, m), 7.32-7.25(1H, m), 1510, 1240 6.85(2H, d, J=9Hz), 6.82(2H,d, J=9Hz), 4.48-4.35(1H, m), 3.87(3H, s), 3.75(2H, s), 3.28(2H, t,J=7Hz), 2.78(3H, s), 2.56-2.46(2H, m), 2.40(2H, ddd, J=11, 11, 3Hz),1.70-1.50(4H, m), 1.67(2H, t, J=7Hz), 1.30(6H, d, J=6Hz) 111  KBr: 1724,CDCl₃: 8.00-7.90(2H, m), 7.57- 53.8- 1510, 1296, 7.52(1H, m), 7.39(1H,dd, J=8, 54.7 1244, 1201, 8Hz), 6.87(2H, d, J=9Hz), 6.83(2H, 1111 d,J=9Hz), 4.50-4.36(1H, m), 3.92(3H, s), 3.56(2H, s), 3.29(2H, t, J=Hz),2.78(3H, s), 2.65- 2.55(2H, m), 2.40(2H, ddd, J=11, 11, 4Hz),1.72-1.55(6H, m), 1.31(6H, d, J=6Hz) 112  liquid film: CDCl₃:7.40-7.29(2H, m), 6.86(2H, oil 2937, 1510, d, J=9Hz), 6.83(2H, d,J=9Hz), 1240, 1113 6.42-6.37(1H, m), 4.50-4.35(1H, m), 3.86(1H, br. s),3.40(2H, s), 3.29(2H, t, J=7Hz), 2.77(3H, s), 2.71-2.58(2H, m), 2.36(2H,ddd, J=11, 11, 4Hz), 1.75-1.55(6H, m), 1.30(6H, d, J=6Hz) 113  liquidfilm: CDCl₃: 7.98(2H, d, J=8Hz), 7.39(2H, oil 1714, 1510, d, J=8Hz),6.88(2H, d, J=9Hz), 1277, 1240, 6.82(2H, d, J=9Hz), 5.30-5.18(1H, 1103m), 4.49-4.37(1H, m), 3.57(2H, s), 3.29(2H, t, J=7Hz), 2.78(3H, s),2.63-2.54(2H, m), 2.40(2H, ddd, J=11, 11, 4Hz), 1.72-1.56(6H, m),1.36(6H, d, J=6Hz), 1.31(6H, d, J=6Hz) 114  liquid film: CDCl₃: 7.99(2H,d, J=8Hz), 7.40(2H, oil 1718, 1510, d, J=8Hz), 6.88(2H, d, J=9Hz), 1275,1240, 6.82(2H, d, J=9Hz), 4.49-4.37(1H, 1111 m), 4.27(2H, t, J=7Hz),3.59(2H, s), 3.29(2H, t, J=7Hz), 2.77(3H, s), 2.66-2.57(2H, m), 2.42(2H,ddd, J=11, 10, 4Hz), 1.85-1.58(8H, m), 1.31(6H, d, J=6Hz), 1.03(3H, t,J=7Hz) 115  liquid film: CDCl₃*: 7.32-7.23(2H, m), 6.98- oil 2937, 1510,6.79(7H, m), 4.50-4.35(1H, m), 1242, 1113, 4.12(2H, t, J=6Hz), 3.98(1H,br. s),  754, 692 3.29(2H, t, J=7Hz), 2.84(2H, t, J=6Hz), 2.80-2.70(2H,m), 2.78(3H, s), 2.54(2H, ddd, J=10, 10, 4Hz), 1.77-1.60(6H, m),1.31(6H, d, J=6Hz) 116  liquid film: CDCl₃*: 7.01-6.78(8H, m), 4.50- oil2937, 1508, 4.35(1H, m), 4.07(2H, t, J=6Hz), 1242, 1209, 3.29(2H, t,J=6Hz), 2.82(2H, t, 1113, 829 J=6Hz), 2.80-2.67(2H, m), 2.78(3H, s),2.52(2H, ddd, J=10, 10, 4Hz), 1.77-1.57(6H, m), 1.31(6H, d, J=6Hz) 117 liquid film: CDCl₃: 7.32-7.13(5H, m), 6.88(2H, oil 2937, 1510, d,J=9Hz), 6.83(2H, d, J=9Hz), 1238, 1115 4.50-4.36(1H, m), 3.29(2H, t,J=6Hz), 2.80-2.60(4H, m), 2.77(3H, s), 2.52-2.36(4H, m), 1.95-1.65(8H,m), 1.31(6H, d, J=6Hz) 118  liquid film: CDCl₃: 7.63-7.25(9H, m),6.86(2H, oil 1510, 1240, d, J=9Hz), 6.82(2H, d, J=9Hz), 1115, 756,4.50-4.35(1H, m), 3.80(1H, br. s),  702 3.59(2H, s), 3.29(2H, t, J=7Hz),2.78(3H, s), 2.70-2.60(2H, m), 2.42(2H, ddd, J=11, 11, 4Hz), 1.75-1.50(6H, m), 1.30(6H, d, J=6Hz) 119  liquid film: CDCl₃*: 7.58-7.50(1H,m), 7.35- oil 2935, 1510, 7.20(8H, m), 6.83(2H, d, J=9Hz), 1240, 752,6.82(2H, d, J=9Hz), 4.50-4.35(1H,  702 m), 3.62(1H, br. s), 3.42(2H, s),3.27(2H, t, J=7Hz), 2.77(3H, s), 2.57-2.45(2H, m), 2.27(2H, ddd, J=11,11, 4Hz), 1.70-1.50(6H, m), 1.30(6H, d, J=6Hz) 120-1 — CDCl₃:7.55-7.46(2H, m), 7.38(1H, — d, J=9Hz), 6.94(2H, d, J=9Hz), 6.84(2H, d,J=9Hz), 5.08(1H, br. s), 4.60-4.38(2H, m), 3.60-3.20(5H, m), 2.77(3H,s), 1.90-1.50(6H, m), 1.31(6H, d, J=6Hz) 120-2 KBr: 2935, CDCl₃:7.55(1H, dd, J=8, 8Hz), 100.2-  1510, 1369, 7.38(1H, d, J=8Hz),7.32-7.26(1H, 101.4 1238, 1115 m), 6.88(2H, d, J=9Hz), 6.82(2H, d,J=9Hz), 4.50-4.36(1H, m), 4.03(1H, br. s), 3.63(2H, s), 3.29(2H, t,J=7Hz), 2.77(3H, s), 2.67-2.57(2H, m), 2.47(2H, ddd, J=11, 11, 3Hz),1.75-1.55(6H, m), 1.31(6H, d, J=6Hz) 121-1 — CDCl₃: 6.91(2H, d, J=9Hz),6.84(2H, — d, J=9Hz), 3.99(2H, q, J=7Hz), 3.29(2H, t, J=7Hz), 3.01(2H,ddd, J=12, 11, 3Hz), 2.85(2H, ddd, J=12, 4, 4Hz), 2.78(3H, s),1.74-1.48(6H, m), 1.39(3H, t, J=7Hz) 121-2 KBr: 1512, CDCl₃*: 7.56(2H,d, J=8Hz), 83.5- 1329, 1244, 7.44(2H, d, J=8Hz), 6.90(2H, d, 84.0 1165,1120 J=9Hz), 6.83(2H, d, J=9Hz), 3.98(2H, q, J=7Hz), 3.56(2H, s),3.29(2H, t, J=6Hz), 2.77(3H, s), 2.67-2.51(2H, m), 2.48-2.32(2H, m),1.76-1.52(6H, m), 1.39(3H, t, J=7Hz) 122-1 — CDCl₃*: 7.35-7.18(6H, m),6.90- — 6.83(1H, m), 6.70-6.60(2H, m), 5.20(1H, s), 4.61-4.48(1H, m),3.47(2H, s), 3.25(3H, s), 2.60- 2.32(4H, m), 2.21(2H, s), 1.71- 1.30(4H,m), 1.36(6H, d, J=5Hz) 122-2 — CDCl₃: 7.35-7.21(5H, m), 7.11(1H, — dd,J=9, 9Hz), 6.40-6.35(1H, m), 6.33-6.28(2H, m), 4.59-4.47(1H, m),3.52(2H, s), 3.47-3.39(2H, m), 2.87(3H, s), 2.67-2.58(2H, m), 2.35(1H,ddd, J=11, 11, 4Hz), 1.75- 1.59(6H, m), 1.33(6H, d, J=6Hz) 122-3 —CDCl₃: 7.13(1H, dd, J=8, 8Hz), — 6.42-6.38(1H, m), 6.34-6.29(2H, m),4.59-4.47(1H, m), 3.49-3.40(2H, m), 3.02-2.80(4H, m), 2.88(3H, s),1.76-1.53(6H, m), 1.33(6H, d, J=6Hz) 122-4 liquid film: CDCl₃: 7.99(2H,d, J=8Hz), 7.40(2H, oil 1722, 1610, d, J=8Hz), 7.12(1H, dd, J=9, 9Hz),1500, 1281, 6.41-6.29(3H, m), 4.59-4.47(1H, m), 1115 3.91(3H, s),3.56(2H, s), 3.43(2H, t, J=7Hz), 2.87(3H, s), 2.65- 2.55(2H, m),2.37(2H, ddd, J=11, 11, 4Hz), 1.77-1.55(6H, m), 1.33(6H, d, J=6Hz) 123-1— CDCl₃*: 7.34-7.18(6H, m), 7.11- — 7.04(1H, m), 6.97-6.88(2H, m),5.34(1H, s), 4.65-4.51(1H, m), 3.47(2H, s), 3.47(2H, s), 3.16(3H, s),2.58-2.45(2H, m), 2.39(2H, ddd, J=11, 11, 3Hz), 2.16(1H, d, J=16Hz),2.07(1H, d, J=16Hz), 1.73- 1.25(4H, m), 1.32(3H, d, J=6Hz), 1.30(3H, d,J=6Hz) 123-2 — CDCl₃: 7.34-7.19(5H, m), 7.08- — 7.00(2H, m),6.90-6.83(2H, m), 4.66-4.54(1H, m), 3.51(2H, s), 3.19(2H, t, J=6Hz),2.67(3H, s), 2.60-2.51(2H, m), 2.41(2H, ddd, J=11, 11, 3Hz),1.72-1.48(6H, m), 1.36(6H, d, J=6Hz) 123-3 — CDCl₃*: 7.09-7.00(2H, m),6.92- — 6.83(2H, m), 4.68-4.53(1H, m), 3.20(2H, t, J=6Hz), 3.04(2H, ddd,J=12, 12, 3Hz), 2.85-2.76(2H, m), 2.68(3H, s), 1.74-1.40(6H, m),1.36(6H, d, J=6Hz) 123-4 liquid film: CDCl₃*: 7.97(2H, d, J=8Hz), oil1722, 1497, 7.40(2H, d, J=8Hz), 7.08-6.99(2H, 1279, 1115 m),6.91-6.82(2H, m), 4.67-4.52(1H, m), 3.90(3H, s), 3.55(2H, s), 3.19(2H,t, J=6Hz), 2.67(3H, s), 2.58-2.37(4H, m), 1.72-1.46(6H, m), 1.36(6H, d,J=6Hz) 124-1 — CDCl₃*: 7.72(1H, br. s), 7.38- — 7.21(7H, m), 6.84(2H, d,J=9Hz), 4.55-4.42(1H, m), 3.93(1H, br. s), 3.53(2H, s), 2.63-2.40(4H,s), 2.47(2H, s), 1.82-1.60(4H, m), 1.31(6H, d, J=6Hz) 124-2 — CDCl₃:7.35-7.22(5H, m), 6.78(2H, — d, J=9Hz), 6.63(2H, d, J=9Hz),4.45-4.32(1H, m), 3.52(2H, s), 3.27(2H, t, J=6Hz), 2.68-2.58(2H, m),2.42-2.30(2H, m), 1.78(2H, t, J=6Hz), 1.74-1.60(4H, m), 1.29(6H, d,J=6Hz) 124-3 — CDCl₃: 6.79(2H, d, J=9Hz), 6.63(2H, — d, J=9Hz),4.45-4.32(1H, m), 3.47(1H, s), 3.28(2H, t, J=6Hz), 2.97(2H, ddd, J=12,12, 3Hz), 2.84(2H, ddd, J=12, 4, 4Hz), 1.79(2H, t, J=6Hz), 1.70-1.48(4H,m), 1.29(6H, d, J=6Hz) 124-4 KBr: 3277, CDCl₃*: 7.98(2H, d, J=8Hz),134.8-  1726, 1512, 7.40(2H, d, J=8Hz), 6.78(2H, d, 135.9 1277, 1113J=9Hz), 6.63(2H, d, J=9Hz), 4.45- 4.30(1H, m), 3.91(3H, s), 3.57(2H, s),3.28(2H, t, J=6Hz), 2.65- 2.55(2H, m), 2.44-2.32(2H, m), 1.78(2H, t,J=6Hz), 1.72-1.63(4H, m), 1.29(6H, d, J=6Hz) 125  KBr: 1510, CDCl₃*:7.57(2H, d, J=8Hz), 152.3-  1333, 1232, 7.45(2H, d, J=8Hz), 6.79(2H, d,153.1 1159, 1122, J=9Hz), 6.63(2H, d, J=9Hz), 4.44- 1099, 1066 4.31(1H,m), 3.57(2H, s), 3.28(2H, t, J=6Hz), 2.67-2.55(2H, m), 2.45- 2.32(2H,m), 1.79(2H, t, J=6Hz), 1.72-1.63(4H, m), 1.29(6H, d, J=6Hz) 126-1 —CDCl₃: 7.45-7.15(10H, m), 6.94(2H, — d, J=8Hz), 6.80(2H, d, J=8Hz),4.66(1H, d, J=12Hz), 4.58-4.46(1H, m), 4.38(1H, d, J=12Hz), 4.28(1H, s),3.81(1H, s), 3.48(2H, s), 3.28(3H, s), 2.68-2.58(2H, m), 2.46-2.27(2H,m), 1.96-1.87(1H, m), 1.57-1.23(9H, m) 126-2 — CDCl₃: 7.12(2H, d,J=9Hz), 6.90(2H, — d, J=9Hz), 4.62-4.47(1H, m), 3.77(1H, s), 3.27(3H,s), 3.00(1H, ddd, J=12, 12, 3Hz), 2.89(1H, ddd, J=12, 12, 3Hz),2.82-2.72(2H, m), 1.82-1.73(1H, m), 1.50-1.15(3H, m), 1.36(6H, d, J=6Hz)126-3 — CDCl₃: 6.87(2H, d, J=9Hz), 6.82(2H, — d, J=9Hz), 4.49-4.36(1H,m), 3.60(1H, dd, J=10, 4Hz), 3.31(1H, dd, J=14, 10Hz), 3.11(1H, dd,J=14, 4Hz), 3.05-2.80(4H, m), 2.81(3H, s), 1.85-1.76(1H, m),1.66-1.40(3H, m), 1.30(6H, d, J =6Hz) 126-4 KBr: 1514, CDCl₃: 7.57(2H,d, J=8Hz), 7.45(2H, 109.0-  1331, 1246, d, J=8Hz), 6.87(2H, d, J=9Hz),110.1 1159, 1120, 6.82(2H, d, J=9Hz), 4.49-4.37(1H, 1066 m), 3.60(1H,dd, J=10, 3Hz), 3.57(2H, s), 3.32(1H, dd, J=13, 10Hz), 3.27(1H, s),3.08(1H, dd, J=13, 3Hz), 2.81(3H, s), 2.73- 2.62(2H, m), 2.46-2.32(2H,m), 2.26(1H, br. s), 1.90-1.80(1H, m), 1.72(1H, ddd, J=13, 13, 5Hz),1.62- 1.50(2H, m), 1.30(6H, d, J=6Hz) 127-1 — CDCl₃: 7.03(2H, d, J=9Hz),6.90(2H, — d, J=9Hz), 4.62-4.50(1H, m), 3.90- 3.65(2H, m), 3.24(3H, s),3.25- 3.10(2H, m), 2.16(2H, s), 1.68- 1.58(2H, m), 1.43(9H, s), 1.37(6H,d, J=6Hz), 1.35-1.18(2H, m) 127-2 — CDCl₃: 7.05(2H, d, J=9Hz), 6.89(2H,— d, J=9Hz), 4.61-4.49(1H, m), 3.90- 3.65(2H, m), 3.22(3H, s), 3.10-2.87(2H, m), 3.04(3H, s), 2.35(2H, s), 1.80-1.64(4H, m), 1.44(9H, s),1.36(6H, d, J=6Hz) 127-3 — CDCl₃: 6.83(2H, d, J=9Hz), 6.69(2H, — d,J=9Hz), 4.45-4.32(1H, m), 3.38- 3.27(2H, m), 3.19(3H, s), 2.96- 2.72(4H,m), 2.84(3H, s), 1.82- 1.62(4H, m), 1.59-1.38(2H, m), 1.30(6H, d, J=6Hz)127-4 liquid film: CDCl₃*: 7.56(2H, d, J=8Hz), oil 1510, 1325, 7.44(2H,d, J=8Hz), 6.82(2H, d, 1240, 1161, J=9Hz), 6.68(2H, d, J=9Hz), 4.45-1122, 1066 4.31(1H, m), 3.53(2H, s), 3.35- 3.27(2H, m), 3.17(3H, s),2.83(3H, s), 2.60-2.48(2H, m), 2.36-2.22(2H, m), 1.86-1.48(6H, m),1.30(6H, d, J=6Hz) 128  liquid film: CDCl₃: 7.98(2H, d, J=8Hz), 7.40(2H,oil 1722, 1510, d, J=8Hz), 6.83(2H, d, J=9Hz), 1279, 1238, 6.68(2H, d,J=9Hz), 4.44-4.32(1H, 1111 m), 3.91(3H, s), 3.54(2H, s), 3.35- 3.27(2H,m), 3.17(3H, s), 2.83(3H, s), 2.58-2.50(2H, m), 2.35-2.24(2H, m),1.85-1.49(6H, m), 1.30(6H, d, J=6Hz) 129-1 liquid film: CDCl₃:7.37-7.21(5H, m), 6.84(2H, oil 1510, 1369, d, J=9Hz), 6.80(2H, d,J=9Hz), 1240, 1113 4.45-4.32(1H, m), 3.53(2H, s), 3.17(2H, s), 2.92(3H,s), 2.74- 2.65(2H, m), 2.36(2H, ddd, J=11, 11, 4Hz), 1.98(1H, s), 1.78-1.60(4H, m), 1.29(6H, d, J=6Hz) 129-2 — CDCl₃: 6.86(2H, d, J=9Hz),6.81(2H, — d, J=9Hz), 4.46-4.32(1H, m), 3.17(2H, s), 3.06-2.85(4H, m),2.94(3H, s), 1.70-1.52(4H, m), 1.29(6H, d, J=6Hz) 129-3 liquid film:CDCl₃*: 7.57(2H, d, J=8Hz), oil 1510, 1325, 7.45(2H, d, J=8Hz), 6.85(2H,d, 1240, 1161, J=10Hz), 6.80(2H, d, J=10Hz), 4.45- 1122, 1066 4.31(1H,m), 3.58(2H, s), 3.18(2H, s), 2.93(3H, s), 2.71-2.62(2H, m), 2.39(2H,ddd, J=11, 11, 4Hz), 2.00(1H, s), 1.78-1.60(4H, m), 1.29(6H, d, J=6Hz)130  liquid film: CDCl₃: 7.99(2H, d, J=8Hz), 7.41(2H, oil 1722, 1510. d,J=8Hz), 6.85(2H, d, J=9Hz), 1281, 1240, 6.80(2H, d, J=9Hz),4.45-4.33(1H, 1113 m), 3.91(3H, s), 3.58(2H, s), 3.18(2H, s), 2.93(3H,s), 2.72- 2.62(2H, m), 2.39(2H, dd, J=11, 11, 4Hz), 1.77-1.60(4H, m),1.29(6H, d, J=6Hz) 131  KBr: 1510, CDCl₃*: 7.41(4H, d, J=7Hz), 7.30-88.6- 1242, 1122, 7.12(6H, m), 6.83(2H, d, J=9Hz), 89.4  708 6.81(2H, d,J=9Hz), 4.48-4.34(1H, m), 4.27(1H, s), 3.59(1H, br. s), 3.29(2H, t,J=7Hz), 2.77(3H, s), 2.65-2.50(2H, m), 2.37-2.22(2H, m), 1.75-1.50(6H,m), 1.30(6H, d, J=6Hz) 132  KBr: 1512, CDCl₃*: 7.33(4H, dd, J=9, 5Hz),oil 1504, 1238, 6.96(4H, dd, J=9, 9Hz), 6.85(2H, d, 1223, 1113, J=9Hz),6.81(2H, d, J=9Hz), 4.48-  841 4.34(1H, m), 4.26(1H, s), 3.80(1H, br.s), 3.28(2H, t, J=7Hz), 2.77(3H, s), 2.58-2.48(2H, m), 2.33-2.20(2H, m),1.73-1.50(6H, m), 1.30(6H, d, J=6Hz) 133  KBr: 1514, CDCl₃:7.44-7.38(4H, m), 7.30- 94.3- 1248, 816, 7.22(4H, m), 7.19-7.13(2H, m),95.8  704 6.86(2H, d, J=9Hz), 6.81(2H, d, J=9Hz), 4.27(1H, s), 3.97(2H,q, J=7Hz), 3.68(1H, br. s), 3.28(2H, t, J=7Hz), 2.76(3H, s),2.63-2.52(2H, m), 2.37-2.21(2H, m), 1.73-1.55(6H, m), 1.38(3H, t, J=7Hz)134  liquid film: CDCl₃: 7.44-7.36(4H, m), 7.30- oil 1610, 1498,7.23(4H, m), 7.20-7.08(3H, m), 1236, 1117, 6.40-6.25(3H, m),4.58-4.46(1H, m),  706 4.26(1H, s), 3.43(2H, t, J=8Hz), 2.86(3H, s),2.66-2.53(2H, m), 2.25(2H, ddd, J=11, 11, 2Hz), 1.80- 1.52(6H, m),1.32(6H, d, J=6Hz) 135  liquid film: CDCl₃*: 7.43-7.35(4H, m), 7.28- oil1495, 1452, 7.10(6H, m), 7.05-6.95(2H, m), 1275, 1232, 6.88-6.79(2H, m),4.63-4.50(1H, m),  744, 706 4.26(1H, s), 3.18(2H, t, J=6Hz), 2.66(3H,s), 2.55-2.44(2H, m), 2.33(2H, ddd, J=11, 11, 3Hz), 1.74- 1.48(6H, m),1.34(6H, d, J=6Hz) 136  KBr: 1512, CDCl₃*: 7.44-7.36(4H, m), 7.30-170.0-  1234, 708 7.13(6H, m), 6.77(2H, d, J=9Hz), 171.2 6.60(2H, d,J=9Hz), 4.43-4.30(1H, m), 4.27(1H, s), 3.26(2H, t, J=6Hz), 2.65-2.53(2H,m), 2.33- 2.20(2H, m), 1.78-1.50(6H, m), 1.28(6H, d, J=6Hz) 137  liquidfilm: CDCl₃: 7.43-7.37(4H, m), 7.29- oil 1510, 1238, 7.22(4H, m),7.19-7.12(2H, m), 1076, 706 6.82(2H, d, J=9Hz), 6.67(2H, d, J=9Hz),4.44-4.32(1H, m), 4.22(1H, s), 3.34-3.25(2H, m), 3.14(3H, s), 2.83(3H,s), 2.58-2.47(2H, m), 2.25-2.12(2H, m), 1.76-1.49(6H, m), 1.30(6H, d,J=6Hz) 138  KBr: 1510, CDCl₃: 7.45-7.38(4H, m), 7.30- amorphous 1240,1113, 7.22(4H, m), 7.20-7.13(2H, m),  706 6.84(2H, d, J=10Hz), 6.80(2H,d, J=10Hz), 4.45-4.26(1H, m), 4.28(1H, s), 3.18(2H, s), 2.92(3H, s),2.72- 2.63(2H, m), 2.32-2.20(2H, m), 1.80-1.53(6H, m), 1.29(6H, d,J=6Hz) 139  liquid film: CDCl₃: 7.35-7.20(5H, m), 6.94(2H, oil 3386,2958, d, J=9Hz), 6.83(2H, d, J=9Hz), 2935, 2872, 3.92(2H, t, J=7Hz),3.52(2H, s), 2814, 1512, 3.24(2H, t, J=6Hz), 3.10(2H, q, 1242, 812,J=7Hz), 2.66-2.55(2H, m), 2.40(2H,  741 ddd, J=11, 11, 3Hz),1.79-1.42(10H, m), 0.97(3H, t, J=7Hz), 0.97(3H, t, J=7Hz) 140  liquidfilm: CDCl₃: 7.57(1H, dd, J=8, 8Hz), oil 2233, 1510, 7.42(1H, dd, J=8,2Hz), 7.32(1H, 1240, 1113 dd, J=9, 2Hz), 6.88(2H, d, J=9Hz), 6.83(2H, d,J=9Hz), 4.50-4.35(1H, m), 3.63(2H, s), 3.28(2H, t, J=7Hz), 2.77(3H, s),2.65-2.55(2H, m), 2.48(2H, ddd, J=11, 11, 3Hz), 1.77-1.56(6H, m),1.31(6H, d, J=6Hz) 141  KBr: 1672, CDCl₃: 7.91(2H, d, J=8Hz), 7.43(2H,82.8- 1605, 1512, d, J=8Hz), 6.88(2H, d, J=9Hz), 84.1 1365, 1271,6.82(2H, d, J=9Hz), 4.50-4.36(1H, 1238, 1113 m), 3.98(1H, br. s),3.57(2H, s), 3.29(2H, t, J=7Hz), 2.78(3H, s), 2.60(3H, s), 2.67-2.53(2H,m), 2.41(2H, ddd, J=11, 11, 3Hz), 1.76- 1.50(6H, m), 1.31(6H, d, J=6Hz)142-1 — CDCl₃: 7.09(2H, d, J=8Hz), 6.86(2H, — d, J=9Hz), 6.81(2H, d,J=9Hz), 6.64(2H, d, J=8Hz), 4.48-4.36(1H, m), 3.61(2H, br. s), 3.41(2H,s), 3.29(2H, t, J=7Hz), 2.78(3H, s), 2.65-2.55(2H, m), 2.33(2H, ddd,J=11, 11, 4Hz), 1.71-1.55(6H, m), 1.30(6H, d, J=6Hz) 142-2 KBr: 1720,CDCl₃: 7.86(1H, br. s), 7.51(2H, d, 38.7- 1512, 1242, J=9Hz), 7.36(2H,d, J=9Hz), 40.1 1157 6.88(2H, d, J=9Hz), 6.82(2H, d, J=9Hz),4.49-4.37(1H, m), 3.52(2H, s), 3.29(2H, t, J=7Hz), 2.77(3H, s),2.66-2.53(2H, m), 2.39(2H, ddd, J=11, 11, 3Hz), 1.74-1.56(6H, m),1.31(6H, d, J=6Hz) 143  KBr: 1599, CD₃OD: 7.91(2H, d, J=8Hz), 7.33(2H,amorphous 1554, 1510, d, J=8Hz), 6.80(2H, d, J=9Hz), 1406, 1240 6.76(2H,d, J=9Hz), 4.47-4.33(1H, m), 3.61(2H, s), 3.40-3.28(2H, m), 2.79(3H, s),2.70-2.43(4H, m), 1.70-1.56(6H, m), 1.25(6H, d, J=6Hz) 146  KBr: 3355,CD₃OD: 7.55-7.47(7H, m), 7.09(2H,   132.8 2948, 2364, d, J=9Hz),4.31(2H, s), 4.01(2H, t, 1512, 1252 J=6Hz), 3.73-3.68(2H, m), 3.31-3.24(4H, m), 3.25(3H, s), 1.85- 1.44(10H, m), 0.98(3H, t, J=7Hz) 162 KBr: 3435, CD₃OD*: 7.61(2H, d, J=9Hz), 7.19- 211 2527, 1512, 7.00(4H,m), 6.93(1H, d, J=8Hz), dec 1495, 1257, 6.04(2H, s), 4.25(2H, s),4.06(2H, 1038 t, J=6Hz), 3.75(2H, t, J=8Hz), 3.50-3.02(4H, m), 3.30(3H,s), 2.13-1.44(10H, m), 1.01(3H, t, J=7Hz) 176  KBr: 3450, DMSO-d₆*:7.84-7.45(2H, m), 207 2956, 2935, 7.30(2H, dd, J=9, 6Hz), 7.16(2H, dec1514, 1259, dd, J=9, 9Hz), 7.15-6.98(2H, m),  837 3.98(2H, t, J=6Hz),3.57-2.90(13H, m), 2.03-1.29(10H, m), 0.92(3H, t, J=7Hz) 177  KBr: 3367,CD₃OD*: 7.69-7.56(4H, m), 7.25(2H, 209 2937, 1514, dd, J=9, 9Hz),7.13(2H, d, J=9Hz), dec 1255, 1226, 4.35(2H, s), 4.06(2H, t, J=6Hz), 839 3.75(2H, t, J=8Hz), 3.38-3.22(4H, m), 3.30(3H, s), 2.16-1.44(10H,m), 1.01(3H, t, J=7Hz) 183  KBr: 3290, CD₃OD*: 7.63(2H, d, J=9Hz), 7.49-209 2567, 1512, 7.33(1H, m), 7.13(2H, d, J=9Hz), dec 1470, 1255,7.06-6.89(2H, m), 4.05(2H, t,  839 J=6Hz), 3.77(2H, t, J=8Hz), 3.59-3.45(2H, m), 3.45-3.20(4H, m), 3.30(3H, s), 3.19-3.03(2H, m),2.14-1.42(10H, m), 1.00(3H, t, J=7Hz) 196  KBr: 3261, CD₃OD*: 7.59(2H,d, J=9Hz), 191.2-  2960, 2575, 7.31(2H, dd, J=9, 5Hz), 7.12(2H, d, 198.71512, 1255, J=9Hz), 7.06(2H, dd, J=9, 9Hz), 1225, 835 4.04(2H, t,J=6Hz), 3.95-3.85(1H, m), 3.69-3.46(3H, m), 3.37-3.19(4H, m), 3.28(3H,s), 3.16-3.03(3H, m), 2.08-1.43(8H, m), 0.99(3H, t, J=7Hz) 198  KBr:3412, CD₃OD*: 7.59(2H, d, J=9Hz), 174.9-  2958, 2468, 7.47(2H, dd, J=9,5Hz), 7.12(2H, 184.5 1512, 1261, dd, J=9, 9Hz), 7.12(2H, d, J=9Hz),1221, 835 5.14(1H, t, J=7Hz), 4.04(2H, t, J=6Hz), 3.75(2H, t, J=8Hz),3.72- 3.46(2H, m), 3.41-3.26(2H, m), 3.29(3H, s), 3.25(2H, d, J=7Hz),2.04-1.44(10H, m), 0.99(3H, t, J=7Hz) 201  KBr: 3431, CD₃OD: 6.59(2H, d,J=9Hz), 7.55- 215 2567, 2492, 7.44(5H, m), 7.11(2H, d, J=9Hz), dec 1514,1470, 4.30(2H, s), 4.02(2H, t, J=6Hz), 1255, 1070 3.68-3.55(2H, m),3.36-3.04(4H, m), 3.27(3H, s), 3.10(3H, s), 2.16- 1.42(10H, m), 0.98(3H,t, J=7Hz) 207  KBr: 1583, CD₃OD*: 7.49(5H, s), 7.15(2H, d, 68.0- 1514,1385, J=9Hz), 6.94(2H, d, J=9Hz), 70.0 1365, 1252, 6.27(4H, s), 4.32(2H,s), 3.95(2H,  864 t, J=7Hz), 3.58-3.45(2H, m), 3.37- 3.22(4H, m),3.02(3H, s), 1.90- 1.60(8H, m), 1.55-1.40(2H, m), 0.97(3H, t, J=7Hz)210  liquid film: CDCl₃*: 7.47-7.37(5H, m), 6.86(2H, oil 1583, 1516, d,J=9Hz), 6.83(2H, d, J=9Hz), 1456, 1356, 6.34(2H, s), 4.17(2H, s),3.90(2H, 1246 t, J=7Hz), 3.45-3.33(2H, m), 3.21(2H, s), 3.18-3.02(2H,m), 2.91(3H, s), 2.12-1.98(2H, m), 1.85-1.40(6H, m), 0.96(3H, t, J=7Hz)220  KBr: 1510, CD₃OD: 7.65(2H, d, J=8Hz), 7.57(2H, 224.4-  1255, 1109,d, J=9Hz), 7.49(2H, d, J=8Hz), 226.2 1012, 955 7.08(2H, d, J=9Hz),4.74-4.58(1H, m), 4.30(2H, s), 3.72(2H, t, s), 2.10-1.50(6H, m),1.32(6H, d, J=6Hz) 221  KBr: 1510, CD₃OD: 7.79(2H, d, J=9Hz), 7.77(2H,241.2-  1325, 1257, d, J=9Hz), 7.53(2H, d, J=9Hz), 242.6 1169, 1130,7.08(2H, d, J=9Hz), 4.72-4.58(1H, 1068 m), 4.42(2H, s), 3.71(2H, t,J=8Hz), 3.35-3.23(4H, m), 3.26(3H, s), 2.10-1.50(6H, m), 1.32(6H, d,J=6Hz) 226  KBr: 2231, CD₃OD: 7.85(2H, d, J=8Hz), 7.76(2H, 220.8-  1510,1257, d, J=8Hz), 7.58(2H, d, J=9Hz), 222.2 1109, 953 7.08(2H, d, J=9Hz),4.73-4.58(1H, m), 4.41(2H, s), 3.71(2H, t, J=8Hz), 3.50-3.10(4H, m),3.26(3H, s), 2.10-1.50(6H, m), 1.32(6H, d, J=6Hz) 233  KBr: 1722, CD₃OD:8.11(2H, d, J=8Hz), 7.67(2H, 218.5-  1512, 1282, d, J=8Hz), 7.52(2H, d,J=8Hz), 219.2 1255, 1109 7.08(2H, d, J=8Hz), 4.72-4.48(1H, m), 4.40(2H,s), 3.92(3H, s), 3.80- 3.63(2H, m), 3.50-3.40(4H, m), 3.26(3H, s),2.10-1.50(6H, m), 1.31(6H, d, J=6Hz) 236  KBr: 1512, CD₃OD: 7.68(2H, d,J=9Hz), 7.55(2H, 233.2-  1263, 1223, d, J=9Hz), 7.42(2H, d, J=9Hz),234.9 1207, 1169 7.08(2H, d, J=9Hz), 4.73-4.58(1H, m), 4.36(2H, s),3.72(2H, t, J=8Hz), 3.50-3.10(4H, m), 3.26(3H, s), 2.10-1.50(6H, m),1.32(6H, d, J=6Hz) 240  KBr: 1608, CD₃OD: 7.63-7.48(5H, m), 7.07(2H,228.3-  1510, 1489, d, J=9Hz), 4.74-4.58(1H, m), 229.1 1255, 1120,4.38(2H, s), 3.72(2H, t, J=8Hz), 1109, 953, 3.50-3.10(4H, m), 3.27(3H,s),  881 2.10-1.50(6H, m), 1.32(6H, d, J=6Hz) 254  KBr: 1512, CD₃OD:7.63(1H, dd, J=5, 1Hz), 216.5-  1255, 1184, 7.58(2H, d, J=9Hz), 7.37(1H,dd, 217.5 1109, 953, J=4, 1Hz), 7.14(1H, dd, J=5, 4Hz),  839 7.08(2H, d,J=9Hz), 4.74-4.58(1H, m), 4.58(2H, s), 3.72(2H, t, J=8Hz), 3.50-3.10(4H,m), 3.27(3H, s), 2.10-1.50(6H, m), 1.32(6H, d, J=6Hz) 278  KBR: 1510,CD₃OD: 7.77-7.71(4H, m), 7.62-   162.7 1456, 1255, 7.36(8H, m), 7.08(2H,d, J=9Hz), dec 1109, 710 5.45(1H, s), 4.75-4.60(1H, m), 3.71(2H, t,J=8Hz), 3.38-3.04(4H, m), 3.26(3H, s), 2.17-1.50(6H, m), 1.32(6H, d,J=6Hz)

[0909] Chemical structures of the compounds in Examples 1 to 289 areshown in Table 7. The abbreviations of the substituents used in the(Chemi(al structures in Table 7 respectively represent substituentsshown in Table 6. TABLE 6 Abbreviation Substituent —Me —CH₃ —tBu—C(CH₃)₃ —Ac —COCH₃ —Boc —COOC(CH₃)₃ —Ph

—Bn

—TBDMS

[0910] TABLE 7 Example 1 Step 1

Example 2 Step 2

Example 2 Step 1

Example 2 Step 2

Example 3 Step 1

Example 3 Step 2

Example 4 Step 1

Example 4 Step 2

Example 5 Step 1

Example 5 Step 2

Example 6 Step 1

Example 6 Step 2

Example 7 Step 1

Example 7 Step 2

Example 8 Step 1

Example 8 Step 2

Example 9 Step 1

Example 9 Step 2

Example 10 Step 1

Example 10 Step 2

Example 11 Step 1

Example 11 Step 2

Example 12 Step 1

Example 12 Step 2

Example 13 Step 1

Example 13 Step 2

Example 14 Step 1

Example 14 Step 2

Example 15

Example 16

Example 17

Example 18

Example 19 Step 1

Example 19 Step 2

Example 20

Example 21

Example 22

Example 23

Example 24

Example 25

Example 26

Example 27

Example 28

Example 29

Example 30

Example 31

Example 32

Example 33 Step 1

Example 33 Step 2

Example 34

Example 35

Example 36

Example 37

Example 38 Step 1

Example 38 Step 2

Example 39 Step 1

Example 39 Step 2

Example 39 Step 3

Example 40 Step 1

Example 40 Step 2

Example 41 Step 1

Example 41 Step 2

Example 42 Step 1

Example 42 Step 2

Example 43 Step 1

Example 43 Step 2

Example 44 Step 1

Example 44 Step 2

Example 45 Step 1

Example 45 Step 2

Example 45 Step 3

Example 46 Step 1

Example 46 Step 2

Example 46 Step 3

Example 46 Step 4

Example 47 Step 1

Example 47 Step 2

Example 48 Step 1

Example 48 Step 2

Example 49 Step 1

Example 49 Step 2

Example 49 Step 3

Example 49 Step 4

Example 49 Step 5

Example 50 Step 1

Example 50 Step 2

Example 50 Step 3

Example 50 Step 4

Example 51 Step 1

Example 51 Step 2

Example 51 Step 3

Example 51 Step 4

Example 52 Step 1

Example 52 Step 2

Example 52 Step 3

Example 53 Step 1

Example 53 Step 2

Example 54

Example 55

Example 56

Example 57

Example 58 Step 1

Example 58 Step 2

Example 58 Step 3

Example 58 Step 4

Example 58 Step 5

Example 59

Example 60

Example 61

Example 62

Example 63

Example 64 Step 1

Example 64 Step 2

Example 65 Step 1

Example 65 Step 2

Example 66 Step 1

Example 66 Step 2

Example 67 Step 1

Example 67 Step 2

Example 68

Example 69

Example 70

Example 71

Example 72 Step 1

Example 72 Step 2

Example 73

Example 74

Example 75

Example 76

Example 77

Example 78

Example 79

Example 80

Example 81

Example 82

Example 83

Example 84

Example 85

Example 86

Example 87

Example 88

Example 89

Example 90

Example 91

Example 92

Example 93

Example 94

Example 95

Example 96

Example 97

Example 98

Example 99

Example 100

Example 101

Example 102

Example 103

Example 104

Example 105

Example 106

Example 107

Example 108

Example 109

Example 110

Example 111

Example 112

Example 113

Example 114

Example 115

Example 116

Example 117

Example 118

Example 119

Example 120 Step 1

Example 120 Step 2

Example 121 Step 1

Example 121 Step 2

Example 122 Step 1

Example 122 Step 2

Example 122 Step 3

Example 122 Step 4

Example 123 Step 1

Example 123 Step 2

Example 123 Step 3

Example 123 Step 4

Example 124 Step 1

Example 124 Step 2

Example 124 Step 3

Example 124 Step 4

Example 125

Example 126 Step 1

Example 126 Step 2

Example 126 Step 3

Example 126 Step 4

Example 127 Step 1

Example 127 Step 2

Example 127 Step 3

Example 127 Step 4

Example 128

Example 129 Step 1

Example 129 Step 2

Example 129 Step 3

Example 130

Example 131

Example 132

Example 133

Example 134

Example 135

Example 136

Example 137

Example 138

Example 139

Example 140

Example 141

Example 142 Step 1

Example 142 Step 2

Example 143

Example 144 dihydrochloride of compound of Example No. 1-2 Example 145dihydrochloride of compound of Example No. 2-2 Example 146dihydrochloride of compound of Example No. 3-2 Example 147dihydrochloride of compound of Example No. 4-2 Example 148dihydrochloride of compound of Example No. 5-2 Example 149dihydrochloride of compound of Example No. 6-2 Example 150dihydrochloride of compound of Example No. 7-2 Example 151dihydrochloride of compound of Example No. 8-2 Example 152dihydrochloride of compound of Example No. 9-2 Example 153dihydrochloride of compound of Example No. 10-2 Example 154dihydrochloride of compound of Example No. 11-2 Example 155dihydrochloride of compound of Example No. 12-2 Example 156dihydrochloride of compound of Example No. 13-2 Example 157dchydrochloride of compound of Example No. 14-2 Example 158dihydrochloride of compound of Example No. 15 Example 159dihydrochloride of compound of Example No. 16 Example 160dihydrochloride of compound of Example No. 17 Example 161dihydrochlorlde of compound of Example No. 18 Example 162dihydrochloride of compound of Example No. 19-2 Example 163dihydrochloride of compound of Example No. 20 Example 164dihydrochloride of compound of Example No. 21 Example 165dihydrochloride of compound of Example No. 22 Example 166dihydrochloride of compound of Example No. 23 Example 167trihydrochloride of compound of Example No. 24 Example 168dihydrochloride of compound of Example No. 25 Example 169dihydrochloride of compound of Example No. 26 Example 170dihydrochloride of compound of Example No. 27 Example 171dihydrochloride of compound of Example No. 28 Example 172dihydrochloride of compound of Example No. 29 Example 173dihydrochloride of compound of Example No. 30 Example 174dihydrochlorlde of compound of Example No. 31 Example 175dihydrochloride of compound of Example No. 32 Example 176dihydrochloride of compound of Example No. 33-2 Example 177dihydrochloride of compound of Example No. 34 Example 178dihydrochloride of compound of Example No. 35 Example 179dihydrochloride of compound of Example No. 36 Example 180dihydrochloride of compound of Example No. 37 Example 181dihydrochloride of compound of Example No. 38-2 Example 182dihydrochloride of compound of Example No. 39-3 Example 183dihydrochloride of compound of Example No. 40-2 Example 184dihydrochloride of compound of Example No. 41-2 Example 185dihydrochloride of compound of Example No. 42-2 Example 186dihydrochloride of compound of Example No. 43-2 Example 187dihydrochloride of compound of Example No. 44-2 Example 188dihydrochloride of compound of Example No. 45-3 Example 189dihydrochloride of compound of Example No. 46-4 Example 190dihydrochloride of compound of Example No. 47-2 Example 191dihydrochloride of compound of Example No. 48-2 Example 192dihydrochloride of compound of Example No. 49-5 Example 193dihydrochloride of compound of Example No. 50-4 Example 194dihydrochloride of compound of Example No. 51-4 Example 195dihydrochloride of compound of Example No. 52-3 Example 196dihydrochloride of compound of Example No. 53-2 Example 197dihydrochloride of compound of Example No. 54 Example 198dihydrochloride of compound of Example No. 55 Example 199monohydrochloride of compound of Example No. 56 Example 200monohydrochloride of compound of Example No. 57 Example 201dihydrochloride of compound of Example No. 58-5 Example 202dihydrochloride of compound of Example No. 59 Example 203dihydrochloride of compound of Example No. 60 Example 204dihydrochloride of compound of Example No. 61 Example 205dihydrochloride of compound of Example No. 62 Example 206dihydrochloride of compound of Example No. 63 Example 207 dimaleate ofcompound of Example No. 3-2 Example 208 monomaleate of compound ofExample No. 3-2 Example 209 monomaleate of compound of Example No. 50-4Example 210 monomaleate of compound of Example No. 59 Example 211dihydrochloride of compound of Example No. 64-2 Example 212dihydrochloride of compound of Example No. 65-2 Example 213dihydrochloride of compound of Example No. 66-2 Example 214dihydrochloride of compound of Example No. 67-2 Example 213dihydrochloride of compound of Example No. 68 Example 216dihydrochloride of compound of Example No. 69 Example 217dihydrochloride of compound of Example No. 70 Example 218dihydrochloride of compound of Example No. 71 Example 219dihydrochloride of compound of Example No. 72-2 Example 220dihydrochloride of compound of Example No. 73 Example 221dihydrochloride of compound of Example No. 74 Example 222dihydrochloride of compound of Example No. 75 Example 223dihydrochloride of compound of Example No. 76 Example 224dihydrochloride of compound of Example No. 77 Example 225dihydrochloride of compound of Example No. 78 Example 226dihydrochloride of compound of Example No. 79 Example 227dihydrochloride of compound of Example No. 80 Example 228dihydrochloride of compound of Example No. 81 Example 229dihydrochloride of compound of Example No. 82 Example 230dihydrochloride of compound of Example No. 83 Example 231dihydrochloride of compound of Example No. 84 Example 232dihydrochloride of compound of Example No. 85 Example 233dihydrochloride of compound of Example No. 86 Example 234dihydrochloride of compound of Example No. 87 Example 235dihydrochloride of compound of Example No. 88 Example 236dihydrochloride of compound of Example No. 89 Example 237dihydrochloride of compound of Example No. 90 Example 238dihydrochloride of compound of Example No. 91 Example 239dihydrochloride of compound of Example No. 92 Example 240dihydrochloride of compound of Example No. 93 Example 241dihydrochloride of compound of Example No. 94 Example 242dihydrochloride of compound of Example No. 95 Example 243dihydrochloride of compound of Example No. 96 Example 244dihydrochloride of compound of Example No. 97 Example 245dihydrochloride of compound of Example No. 98 Example 246dihydrochloride of compound of Example No. 99 Example 247dihydrochloride of compound of Example No. 100 Example 248dihydrochloride of compound of Example No. 101 Example 249dihydrochloride of compound of Example No. 102 Example 250dihydrochloride of compound of Example No. 103 Example 251dihydrochloride of compound of Example No. 104 Example 252dihydrochloride of compound of Example No. 105 Example 253dihydrochloride of compound of Example No. 106 Example 254dihydrochloride of compound of Example No. 107 Example 255dihydrochloride of compound of Example No. 108 Example 256dihydrochloride of compound of Example No. 109 Example 257dihydrochloride of compound of Example No. 110 Example 258dihydrochloride of compound of Example No. 111 Example 259dihydrochloride of compound of Example No. 112 Example 260dihydrochloride of compound of Example No. 113 Example 261dihydrochloride of compound of Example No. 114 Example 262dihydrochloride of compound of Example No. 115 Example 263dihydrochloride of compound of Example No. 116 Example 264dihydrochloride of compound of Example No. 117 Example 265dihydrochloride of compound of Example No. 118 Example 266dihydrochloride of compound of Example No. 119 Example 267dihydrochloride of compound of Example No. 120-2 Example 268dihydrochloride of compound of Example No. 121-2 Example 269dihydrochloride of compound of Example No. 122-4 Example 270dihydrochloride of compound of Example No. 123-4 Example 271dihydrochloride of compound of Example No. 124-4 Example 272dihydrochloride of compound of Example No. 125 Example 273dihydrochloride of compound of Example No. 126-4 Example 274dihydrochloride of compound of Example No. 127-4 Example 275dihydrochloride of compound of Example No. 128 Example 276dihydrochloride of compound of Example No. 129-3 Example 277dihydrochloride of compound of Example No. 130 Example 278dihydrochloride of compound of Example No. 131 Example 279dihydrochloride of compound of Example No. 132 Example 280dihydrochlorlde of compound of Example No. 133 Example 281dihydrochloride of compound of Example No. 134 Example 282dihydrochloride of compound of Example No. 135 Example 283dihydrochloride of compound of Example No. 136 Example 284dihydrochloride of compound of Example No. 137 Example 285dihydrochloride of compound of Example No. 138 Example 286dihydrochloride of compound of Example No. 139 Example 287dihydrochloride of compound of Example No. 140 Example 288dihydrochloride of compound of Example No. 141 Example 289dihydrochloride of compound of Example No. 142-2

Example of Formulation

[0911] Examples of formulation containing the compounds according to thepresent invention are shown below. However, the present invention is byno means restricted to these examples. (Formulation Example 1: Tablet)The compound in the Example 146 100 g Lactose 350 g Potato starch 120 gPolyvinyl alcohol  15 g Magnesium stearate  15 g

[0912] After weighing each component above, the compound in the Example146, lactose and potato starch are homogeneously mixed. An aqueoussolution of polyvinyl alcohol is added to this mixture, and granules areprepared by a wet granulation method. The granules are dried, mixed withmagnesium stearate, and formed into tablets each weighing 300 mg bypress-molding. (Formulation Example 2: Capsules) The compound in theExample 177  50 g Lactose 435 g Magnesium stearate  15 g

[0913] The components above are homogeneously mixed after weighing.Three hundred milligram each of the mixture is filled in an appropriatehard capsule by using a capsule-encapsulating machine to prepare acapsule drug. (Formulation Example 3: Injections) The compound in theExample 210  2 g Propylene glycol 200 g Distilled water for injectionproper volume

[0914] The compound in the example 210 is dissolved in propylene glycolafter weighing each component. Aseptic water for injection is added tomake a total volume of 1000 mL, and 5 mL each of the aqueous solution isdispensed in a 10 mL ampoule after aseptic filtration, followed byfusing the ampoule to prepare an injection. (Formulation Example 4:Suppository) The compound in the Example 198 100 g Polyethylene glycol1500 180 g Polyethylene glycol 4000 720 g

[0915] After grinding the compound in the example 198 in a mortar intofine powder, suppositories each weighing 1 g are prepared byhot-melting. (Formulation Example 5: Powder) The compound in the Example162 200 g Lactose 790 g magnesium stearate  10 g

[0916] A powder containing 20% of the effective ingredient is preparedby mixing each component homogeneously after weighing.

Industrial Applicability

[0917] The compounds according to the present invention showedeffectiveness in the arrhythimia model of animals and did not almostaffect on the electrocardiogram of normal animals, and therefore theyare useful as preventive and/or therapeutic agents of arrhythimia thatdo not suppress transient sodium current of the cardiac muscle and donot manifest proarrhythimic activity, and agents for preventing suddendeath.

[0918] In the disease conditions of atrial flutter and atrialfibrillation, atrial flutter and atrial fibrillation are liable to occurby onset of electrical remodeling due to atrial flutter and atrialfibrillation themselves. No clinical applications of the drugs forsuppressing electrical remodeling have been carried out, and excessinflux of sodium and calcium is suggested as the cause of thisphenomenon. Veratrine generates, or the other hand, a persistent sodiumcurrent by suppressing inactivation of the sodium channel incorporatedin the cardiac muscle cells. Consequently, since veratrine causescontracture as a result of increased intracellular sodium concentrationfollowed by increased intracellular calcium concentration through asodium/calcium exchange transport system, the compounds according to thepresent invention seem to suppress the persistent sodium current.Judging from these facts, the compounds according to the presentinvention that suppress excess sodium influx caused by the persistentsodium current are useful for preventing progress of disease conditionsof atrial flutter and atrial fibrillation.

[0919] The compounds according to the present invention has an action tosuppress contracture of the isolated cardiac muscle cells as well aspersistent sodium current. Therefore, the compounds according to thepresent invention are effective for therapy and alleviation of symptomssuch as heart failure, angina pectoris, myocardial infarction,cardiovascular disorder accompanied with revascularization byPTCA/PTCR/CABG, injury of cardiomyocytes caused by ischemia-reperfusion(except severe arrhythimia), acute phase of cerebral infarction,cerebral hemorrhage transient cerebral ischemia, subarachnoidhemorrhage, head trauma, sequela of surgical operation of the brain,cerebrovascular disorder such as sequela of cerebral arteriosclerosis,disorder of implanted organs after implantation, syndromes caused bytemporary shut-down of the flood stream in surgical operation of theorgans, convulsion, epilepsy, cerebrovascular dementia and seniledementia, neuralgia, migraine, neuropathic pain, intoxication bydigitalis, monkshood or pyrethroid insecticides. The compounds accordingto the present invention are also applicable to hyperkalemic periodicparalysis that is a congenital disease caused by the persistent sodiumcurrent, myotonia congenital and long QT syndrome.

What is claimed is:
 1. A compound represented by the following formula(I):

(wherein A represents a phenyl group, naphthyl group or monocyclicaromatic heterocyclic group each substituted by R¹ and R²; R¹ and R²each independently represent groups arbitrarily selected from a groupcomprising hydrogen atom, halogen atom, trifluoromethyl group, cyanogroup, lower alkoxycarbonyl group, amino group unsubstituted or mono- ordi-substituted by lower alkyl group, lower alkanoylamino groupunsubstituted or substituted by fluorine atom, unprotected or protectedhydroxyl group lower alkoxy group, lower alkyl group, trifluoromethoxygroup, nitro group, phenyl group, phenoxy group, unprotected orprotected carboxyl group, carbamoyl group unsubstituted or mono- ordi-substituted by lower alkyl group, lower alkanoyl group, loweralkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl groupand sulfamoyl group unsubstituted or mono- or di-substituted by loweralkyl group, or R¹ and R² together represent alkylenedioxy group; R³represents hydrogen atom or lower alkyl group; R⁴ represents hydrogenatom, lower alkyl group or lower alkanoyl group; R⁵ and R⁶ eachindependently represent a group arbitrarily selected from a groupcomprising hydrogen atom, halogen atom, lower alkoxy group unsubstitutedor mono-substituted by unprotected or protected hydroxyl group, loweralkyl group unsubstituted or mono-substituted by unprotected orprotected hydroxyl group, phenoxy group, lower alkenyloxy group orunprotected or protected hydroxyl group; X represents a single bond, agroup: —CH(OH)—, oxygen atom or carbonyl group; Y represents loweralkylene group, lower alkylidene group or benzylidene group substitutedby R¹, Y may form 5 or 6-membered ring together with X and carbon atomson a benzene ring when A is phenyl group; Z represents a single bond ormethylene group unsubstituted or substituted by a group arbitrarilyselected from a group comprising lower alkyl group, lower alkoxy groupor unprotected or protected hydroxyl group; and R⁷ and R⁸ eachindependently represent hydrogen atom or lower alkyl groups, providedthat a case that R⁵ and R⁶ simultaneously represent hydrogen atoms isexcluded) and a salt thereof.
 2. A compound or a salt thereof as claimedin claim 1, wherein the binding position of R⁵ is a para-position(4-position) relative to —NR⁴—, R⁷ and R⁸ each represent hydrogen atom,X is a single bond, and Y represents C₁ or C₂ alkylene group orbenzylidene group substituted by R¹.
 3. A compound or a salt thereof asclaimed in claim 1 or 2, wherein A represents phenyl group or thienylgroup each substituted by R¹ and R², Z is a single bond or methylenegroup.
 4. A compound or a salt thereof as claimed in claims 1 to 3,wherein R¹ represents hydrogen atom, halogen atom, trifluoromethylgroup, cyano group, lower alkoxycarbonyl group or trifluoromethoxygroup, R² represents hydrogen atom or halogen atom, R³ representshydrogen atom, R⁵ represents C₂₋₆ alkoxy group, R⁶ represents hydrogenatom, Y represents methylene group or benzylidene group substituted byR¹.
 5. A compound or a salt thereof as claimed in claim 1, wherein thecompound or the salt is selected from1-benzyl-4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-piperidin-4-ol;1-benzyl-4-[2-[N-methyl-N-(4-n-propoxylphenyl)amino]ethyl]-piperidin-4-ol;4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(4-chloro-phenylmethyl)piperidin-4-ol;4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-[4-trifluoromethyl)phenylmethyl]piperidin-4-ol;4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(4-cyano-phenylmethyl)piperidin-4-ol;4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(4-methoxycarbonylphenylmethyl)piperidin-4-ol;4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(3-fluoro-phenylmethyl)piperidin-4-ol;4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(3,4-difluorophenylmethyl)piperidin-4-ol;4[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(4-fluorophenylmethyl)piperidin-4-ol;4[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(2-fluorophenylmethyl)piperidin-4-ol;1-(4-chlorophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol;1-(4-bromophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol;4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-(4-trifluoromethyl)phenylmethyl]piperidin-4-ol;1-(4-fluorophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol;1-(4-cyanophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol;4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-(4-nitrophenylmethyl)piperidin-4-ol;1-[4-(methoxycarbonyl)phenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol;1-[4-fluoro-3-(trifluoromethyl)phenylmethyl)-4-[2-[N-methyl-N-4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol;1-(4-bromo-2-fluorophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol;4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-(2-thienylmethyl)piperidin-4-ol;1-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-(3-thienylmethyl)piperidin-4-ol;1-[2-(methoxycarbonyl)phenylmethyl]-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol;1-[3-(methoxycarbonyl)phenylmethyl]-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol;4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-(4-isopropoxycarbonyl)phenylmethyl]piperidin-4-ol;1-[2-fluoro-4-trifluoromethyl)phenylmethyl]-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl)piperidin-4-ol;4-[2-[N-methyl-N-(4-ethoxyphenyl)amino]ethyl]-1-[4-(trifluoromethyl)phenylmethyl]piperidin-4-ol;1-diphenylmethyl-4-[2-[N-methyl-N-(4-isopropoxyphenyl)-amino]ethyl]piperidin-4-ol;1-bis(4-fluorophenylmethyl-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol;and1-diphenylmethyl-4-[2-[N-(4-ethoxyphenyl)-N-methylamino]-ethyl]piperidin-4-ol.6. Pharmaceutical compositions characterized by containing the compoundrepresented by the formula (I) as described in claim 1 orpharmaceutically acceptable salt thereof.
 7. Antiarrhythmic agentcharacterized by containing the compound represented by the formula (I)as described in claim 1 or pharmaceutically acceptable salt thereof.